Advancements in Nanomedicine for Precision Management of Lymphoma: Mechanisms, Diagnostics, and Therapeutic Strategies

Introduction

Lymphoma comprises a group of malignant tumors originating from the lymphohematopoietic system,¹ representing a significant global public health challenge.^2,3 According to recent data from the World Health Organization (WHO), lymphoma ranks among the most prevalent hematologic malignancies, characterized by high incidence and mortality rates, thus underscoring the urgent need for more effective therapeutic strategies.^4,5 Although Hodgkin lymphoma (HL) is relatively less common, its incidence in young adults remains a clinical concern. The pathogenesis of lymphoma is multifactorial, involving complex interactions among genetic susceptibility,⁶ immune dysregulation,⁷ infections by specific pathogens⁸ (eg, Epstein-Barr virus (EBV)^9,10 and Helicobacter pylori¹¹), and environmental exposures.¹² Despite considerable progress in chemoimmunotherapy, targeted agents, and cellular therapies, clinical management of lymphoma still faces substantial challenges. Conventional chemotherapy regimens, exemplified by R-CHOP, are clinically effective^13,14 but frequently cause significant adverse effects, including cardiotoxicity and myelosuppression. Targeted therapies, such as the anti-CD20 monoclonal antibody rituximab, have transformed treatment strategies for B-cell lymphomas; however, primary and secondary resistance pose growing limitations.¹⁵ Immunotherapies, particularly Chimeric antigen receptor (CAR)-T-cell therapy, represent a major breakthrough,^16–18 but their application is limited by toxicities such as cytokine release syndrome (CRS), restricted efficacy in immunosuppressive tumor microenvironments (TME), and high treatment costs.^19,20 These challenges collectively underscore the urgent need for novel therapeutic strategies offering enhanced targeting, improved safety, and the ability to overcome drug resistance.

Due to these pressing challenges in lymphoma treatment, innovative therapeutic approaches are urgently required. Nanomedicine, an interdisciplinary research field integrating materials science, biomedicine, and engineering, provides a promising foundation for precise lymphoma diagnosis and treatment. Nanomedicine utilizes engineered nanocarriers to achieve targeted delivery and precise spatiotemporal control of anticancer agents, thus improving therapeutic efficacy while minimizing off-target toxicities in lymphoma therapy.^21,22 Moreover, the unique physicochemical and biocompatible properties of nanomaterials facilitate real-time, dynamic monitoring and imaging of lymphoma progression at molecular and cellular levels. These capabilities provide a robust foundation for novel theranostic platforms that integrate diagnosis and therapy.

Notably, nanomedicine holds significant potential for addressing lymphoma heterogeneity and drug resistance through innovative strategies. Nanoparticles engineered with multi-stage responsiveness allow precise interventions tailored to lymphoma subtypes and distinct microenvironmental features.^23,24 Additionally, nanoprobes functionalized with aptamers or specific ligands enable highly sensitive detection of lymphoma biomarkers, including circulating tumor DNA and exosomes. These probes represent powerful new tools for early diagnosis and disease recurrence monitoring.^25–27 Therapeutically, nanomedicine has advanced immunotherapeutic and combinational strategies. Nanocarriers can deliver immunomodulatory agents directly to tumor-associated immune cells, effectively reprogramming the tumor immune microenvironment to enhance treatment outcomes.²⁸ Moreover, co-loading chemotherapeutics with photothermal agents facilitates synergistic therapies, such as chemo-photothermal therapy (PTT), significantly improving antitumor outcomes.²⁹ With ongoing advancements in nanotechnology, lymphoma treatment holds substantial promise for developing more effective, personalized, and less toxic therapeutic approaches.

This review systematically summarizes and critically examines recent advances in nanomedicine for lymphoma, focusing on its applications in diagnostic innovation, therapeutic optimization, immune modulation, and the development of integrated theranostic platforms. Additionally, prevailing clinical translation challenges are discussed, and perspectives are provided on how nanomedicine may shape future precision medicine approaches for lymphoma.

Pathological Basis of Lymphoma and Interventional Principles of Nanomedicine

Lymphoma exhibits distinct pathophysiological features that pose considerable challenges in clinical management but also provide specific targets for novel diagnostic and therapeutic strategies (Figure 1). Nanomedicine, as a highly interdisciplinary field, aims for precise interventions at key pathological nodes through advanced engineering approaches based on an in-depth understanding of disease mechanisms. This chapter systematically reviews the pathological foundations of lymphoma and outlines core nanomedicine design principles to address these challenges.

Figure 1 Pathological features of lymphoma and nanomedicine interventions. This figure illustrates the primary pathological characteristics of lymphoma, emphasizing the distinct structural and functional abnormalities underlying disease progression. Lymphoma is characterized by altered immune cell proliferation and migration, leading to enlarged lymph nodes and disrupted tissue architecture. The lymphatic system, central to lymphoma initiation and advancement, is presented in detail, highlighting primary and secondary lymphoid organs, such as the thymus, spleen, and various lymph nodes. These organs exhibit characteristic pathological changes, including immune cell infiltration and tumor cell localization, providing potential targets for therapeutic interventions. Nanomedicines, with their precise targeting capabilities, offer novel insights into lymphoma diagnosis and treatment. This figure illustrates the key biological barriers within the lymphatic system and corresponding adaptive properties required of nanocarriers, highlighting essential design criteria for lymphoma interventions. This provides a theoretical basis for developing lymphatic system-targeted nanotheranostic platforms. Reproduced from,30 Copyright © 2023 by the authors.

Molecular Genetic Heterogeneity and Precision Targeting Interventions

Lymphomagenesis and progression typically involve multiple genetic alterations, including chromosomal translocations, gene mutations, copy number variations, and dysregulated epigenetic modifications.^31,32 Among B-cell lymphomas, Diffuse Large B-cell Lymphoma (DLBCL), the most common aggressive subtype, can be further classified according to cell of origin (eg, Germinal Center B-cell-like and non-GCB subtypes), corresponding to significant differences in prognosis and responses to the standard R-CHOP regimen (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, Prednisone).³³ Indolent B-cell lymphomas, such as Follicular Lymphoma (FL), frequently carry the t(14;18) translocation, resulting in BCL2 overexpression.^34,35 Their transformation into more aggressive DLBCL poses a major clinical concern. Mantle Cell Lymphoma (MCL) is aggressive and generally incurable, characterized by Cyclin D1 overexpression due to the t(11;14) translocation.³⁶ Conversely, T-cell and NK-cell lymphomas, though rare, are often highly aggressive and exhibit poor sensitivity to conventional chemotherapy, resulting in an unfavorable prognosis. A prominent example is Extranodal NK/T-cell Lymphoma, strongly associated with EBV infection and typically requiring treatment with asparaginase-containing, non-anthracycline-based regimens.^37,38

The molecular and genetic heterogeneity of lymphoma is further manifested by aberrant expression of specific surface antigens on tumor cells. The expression profiles of these antigenic markers closely correlate with underlying genetic driver events, providing a fundamental basis for the precise targeting by nanosystems. The CD19-encoding gene is not directly mutated, but is constitutively expressed in B-cell lymphoma due to dysregulated genetic pathways during B-cell development, serving as a characteristic target in B-cell malignancies. Its stable expression is tightly associated with specific genetic backgrounds.³⁹ CD20, a critical B-cell surface marker, is regulated by complex mechanisms including transcriptional regulation, epigenetic modifications, and signals from the tumor microenvironment, causing substantial variability in its expression across B-cell lymphoma subtypes. Monoclonal antibodies targeting CD20 (eg, rituximab) represent the first clinically successful targeted therapies for lymphoma, significantly reshaping therapeutic strategies for B-cell malignancies. Nevertheless, CD20 expression can be downregulated by gene mutations, epigenetic alterations, or therapeutic selection pressure, significantly contributing to clinical drug resistance.⁴⁰

CD30 is aberrantly overexpressed in Hodgkin and Reed-Sternberg (HRS) cells in Hodgkin lymphoma (HL) and in anaplastic large cell lymphoma (ALCL), while its expression in normal lymphoid tissue remains very low, thus serving as a crucial tumor-specific target. In ALK-positive ALCL, the t(2;5) translocation generates the NPM-ALK fusion protein, which elevates JunB transcription factor expression, subsequently activating CD30 transcription.⁴¹ In diffuse large B-cell lymphoma (DLBCL), high CD38 expression significantly correlates with enhanced proliferation and poor prognosis, promoting tumor cell proliferation and facilitating immune evasion. Monoclonal antibodies targeting CD38 have shown therapeutic efficacy in other hematological malignancies, and preclinical studies support their potential in DLBCL, providing a promising targeted option for relapsed and refractory patients.⁴² CD70 is aberrantly overexpressed in various lymphoma types due to activated NF-κB signaling, contributing to tumor immune evasion and emerging recently as a genetically regulated target.⁴³ The expression patterns of these markers reflect lymphoma-specific genetic features, demonstrate high tumor specificity, and correlate closely with pathological progression, thus providing well-defined anchors for the surface modification of nanocarriers.

These driver genetic abnormalities form the basis for precise diagnosis and classification, while also requiring highly specific therapeutic strategies. Accordingly, nanomedicine’s interventional rationale focuses on overcoming heterogeneity-driven drug resistance. Functionalized nanocarriers are designed to achieve two primary objectives: first, surface modification with specific ligands (eg, antibodies, aptamers) enables active recognition and accumulation in lymphoma cells expressing targets such as CD19, CD20, or CD30, facilitating targeted drug delivery;^44,45 second, they act as delivery platforms for therapeutic nucleic acids (eg, siRNA, mRNA), protecting these molecules from degradation, enhancing cellular uptake, and allowing direct silencing of oncogenes such as BCL2 or Cyclin D1, or expressing therapeutic proteins—thus enabling precision intervention at the molecular level.⁴⁶

TME, Immune Evasion Mechanisms, and Intelligent Responsive Design

The biological behavior and treatment response of lymphoma are strongly affected by its TME.⁴⁷ The lymphoma TME is a complex pathological ecosystem composed of diverse immune cells (including regulatory T cells, tumor-associated macrophages, and myeloid-derived suppressor cells), stromal cells, vascular networks, extracellular matrix, and abundant signaling molecules (such as cytokines and chemokines).^48–50 This milieu is often profoundly immunosuppressive. In Classical HL, for instance, the TME mediates immune suppression through multiple mechanisms.⁵¹ Studies have shown that significant PD-L1 expression in the TME originates from tumor-associated macrophages. Together with tumor-cell PD-L1, these macrophages spatially envelop Hodgkin and Reed-Sternberg (HRS) cells and accumulate at interfaces with PD-1+ T cells (including CD4+ T cells). This arrangement creates a topological structure that inhibits anti-tumor T-cell function.⁵² Moreover, the TME commonly fosters immune escape across various lymphoma subtypes by establishing an immunosuppressive barrier. In FL, for example, the TME is enriched with functionally exhausted cytotoxic T cells, immunosuppressive regulatory T cells, and reprogrammed follicular helper T cells. Together, these cells form a tumor-permissive niche. This dynamic network of immunosuppressive cells, characterized by extensive crosstalk and interdependence with tumor cells, underpins immune evasion and tumor growth.^53,54 Additionally, aberrant vascular structures and high interstitial fluid pressure within the TME create major physical barriers to drug delivery.⁵⁵

Given the pivotal role of the TME in driving therapeutic resistance, it has emerged as an ideal target for nanotechnology-enabled active targeting and immune modulation. To address TME complexity, nanomedicine design generally follows two core principles: intelligent responsiveness and active remodeling.

Intelligent responsiveness refers to the ability of nanocarriers to sense and respond to specific physicochemical cues within the TME, enabling precise spatiotemporal control of drug release. For example, nanocarriers can incorporate pH-responsive materials, such as liposomes or polymers containing hydrazone bonds, which undergo structural changes and release their payload under the mildly acidic conditions characteristic of the TME.^56,57 Alternatively, nanocarriers may be engineered to respond to enzymes overexpressed in the TME, such as matrix metalloproteinases, thereby enabling enzyme-triggered drug release at tumor sites.^58,59 Collectively, these smart-responsive strategies enhance tumor-selective drug accumulation while reducing systemic toxicity.^60,61 Active remodeling strategies aim to directly reprogram the immunosuppressive landscape of the TME via targeted delivery of immunomodulatory agents using nanocarriers.⁶² For instance, surface-functionalized nanocarriers can selectively target tumor-associated macrophages or regulatory T cells, delivering small-molecule inhibitors, like CSF-1R inhibitors, to suppress their immunosuppressive functions.⁶³ Similarly, cytokines (eg, IL-12) or immune agonists (eg, STING agonists) can be delivered to antigen-presenting cells, promoting their activation and initiating robust antitumor T-cell responses.⁶⁴ Through these integrated approaches, nanomedicine-based strategies can effectively counteract TME-mediated immunosuppression, ultimately transforming the TME into a supportive niche for immune-driven tumor eradication.

Disseminated Distribution, Systemic Dissemination Patterns, Diagnosis, and Therapy

In sharp contrast to most solid tumors, lymphoma exhibits inherently disseminated distribution and dependence on the lymphatic network.^65–67 As a cancer of the immune system, lymphoma cells often follow the native “homing” and migration pathways of lymphocytes. This enables widespread infiltration of lymphoid organs (including lymph nodes, spleen, and bone marrow) early in disease progression. Systemic dissemination through lymphatic and hematogenous routes leads to multiple lesions.^68,69 This distinctive dissemination pattern poses two central challenges. First, conventional imaging techniques lack sensitivity for early detection of millimeter-scale micro-infiltrates. Single-site biopsies also fail to capture the extent of systemic disease spread and spatial heterogeneity. Multi-region genomic sequencing in DLBCL has revealed significant inter-regional mutational diversity within individual tumors. Thus, reliance on a single biopsy systematically underestimates genomic complexity and potential resistance mechanisms.^70,71 Second, conventional chemotherapeutic and targeted agents often fail to reach effective concentrations in disseminated lesions after systemic administration. This limitation particularly affects “immune sanctuary sites” protected by blood-tissue barriers (such as the blood-brain and blood-testis barriers), including the central nervous system (CNS).⁷² This limitation results in high relapse rates within these sanctuaries. For example, in aggressive blastoid variant MCL, CNS relapse is a major contributor to high mortality. Case reports document CNS recurrence even after standard chemotherapy, necessitating salvage therapy with blood-brain barrier-penetrating BTK inhibitors (such as ibrutinib).⁷³

Consequently, nanocarriers capable of systemic delivery and preferential accumulation in lymphoid tissues, via the Enhanced Permeability and Retention (EPR) effect or active targeting, represent a promising solution. Nanomedicine thus paves the way for innovative systemic theranostic approaches. For diagnosis, functionalized nanoprobes serve as “systemic scouts,” enabling non-invasive liquid biopsy and highly sensitive imaging of micro-metastases by detecting circulating tumor-derived components or acting as advanced contrast agents.⁷⁴ For treatment, through meticulous size control and surface engineering, nanocarriers facilitate systemic drug delivery and targeted accumulation at disease sites. This approach may systematically eradicate disseminated tumor cells and overcome barriers presented by anatomical sanctuaries that conventional drugs cannot reach.⁷⁵

Application of Nanomedicine in Lymphoma Diagnosis

Lymphoma, a group of malignancies originating from the hematopoietic system, presents diagnostic complexities exceeding those of conventional solid tumors. This complexity mainly results from diffuse tumor distribution and high heterogeneity. The current diagnostic gold standard still relies on histopathological biopsy combined with flow cytometry and molecular genetic analysis. However, this invasive approach has inherent limitations, including unavoidable sampling errors. Such errors occur particularly when malignant cells are unevenly distributed, making single-site biopsies insufficient to capture the complete disease profile.^70,76 Moreover, spatiotemporal heterogeneity in lymphoma can result in clonal evolution during treatment. Consequently, the initial pathological profile may not accurately reflect relapsed or refractory disease.^77–79 Currently, nanomaterial-based research has increasingly been applied to lymphoma diagnosis. In imaging assessment, positron emission tomography (PET-CT) plays a central role in lymphoma staging and treatment response evaluation, but its reliance on glucose metabolic activity lacks disease specificity.^80,81 False positives may occur due to inflammation, infection, or benign conditions, while some low-grade lymphoma subtypes yield false negatives. Moreover, PET-CT’s spatial resolution limits hinder detection of sub-millimeter minimal residual disease or micrometastases, directly affecting treatment timing and prognostic accuracy.^82,83 Magnetic resonance imaging (MRI) offers superior soft-tissue resolution, but conventional gadolinium-based contrast agents have limited capability to differentiate benign from malignant lymph nodes, especially reactive hyperplasia from early malignant infiltration.⁸⁴

Molecular diagnostics (such as PCR and next-generation sequencing) can provide information on genetic rearrangements and mutations.⁸⁵ However, these methods also depend on tissue samples, fail to resolve tumor heterogeneity, and have limited sensitivity for minimal residual disease monitoring.⁷¹ Additionally, lengthy turnaround times limit their clinical utility in rapid decision-making. Consequently, a clear technological gap exists in lymphoma diagnostics: there is an urgent demand for non-invasive, real-time monitoring tools capable of systemic screening, high-sensitivity detection, and molecular subtyping guidance. This unmet need creates fertile ground for nanotechnology applications in lymphoma diagnosis (Table 1).

Table 1 Applications of Nanotechnology in Lymphoma Diagnosis

Extracellular Vesicle Targeted Detection Technologies

EVs have emerged as promising diagnostic targets in lymphoma due to their rich molecular content derived from parental cells, including surface markers and physicochemical properties.^99–101 Targeted EV detection technologies have been systematically developed. For example, researchers created a method integrating Fe₃O₄@TiO₂ magnetic bead enrichment with CuCo-ZIF/Pt nanozyme multimodal sensing. This approach enables rapid EV isolation and dual-mode colorimetric and fluorescent detection of CD20. Coupled with a Resnet18-DA neural network model, this system achieved nearly 100% accuracy in determining CD20 concentration via color response.⁸⁶ To further improve sensitivity, a Lewis acid-enhanced Ce/UiO-67 nanozyme electrochemical immunosensor was developed for CD20 detection on EVs. This method demonstrated a detection range of 5.12×10² to 1.6×10⁷ particles/μL and a detection limit of 280 particles/μL, effectively distinguishing plasma samples from lymphoma patients and healthy individuals.⁸⁷ Beyond chemical markers, EV physical properties also hold diagnostic potential. Atomic force microscopy (AFM) analysis of EVs from blood cancer patients revealed significant nanomechanical differences between lymphoma patients and healthy volunteers. This provides novel mechanical biomarkers for liquid biopsy in hematologic cancers.¹⁰² These advancements enhance EV detection sensitivity and clinical applicability from both chemical and physical perspectives, laying the groundwork for early lymphoma diagnosis.

High-Sensitivity Nucleic Acid Biomarker Detection Systems

Nucleic acid biomarkers offer distinct advantages in lymphoma diagnosis and prognosis. High-sensitivity detection systems for these biomarkers have achieved multi-dimensional breakthroughs.^103–105 For microRNA (miRNA) detection, researchers developed a black phosphorus (BP)-enhanced fiber-optic surface plasmon resonance sensor integrated with the CRISPR-Cas13a system to detect PCNSL-associated miRNAs. This amplification-free method achieved a detection limit of 21 aM and demonstrated applicability for clinical aqueous humor samples.⁸⁸ Similarly, for lymphoma-associated miR-21, a gold nanoconical array (Au-NCA) SERS biosensor was constructed, achieving a detection limit of 3.02 aM and producing results consistent with conventional methods in patient serum samples.⁸⁹

Beyond circulating miRNAs, cerebrospinal fluid (CSF) cell-free DNA (cfDNA) analysis provides new avenues for diagnosing central nervous system lymphoma. Nanopore sequencing of CSF cfDNA has addressed diagnostic challenges in cytology-negative lymphoma cases. Researchers successfully diagnosed intravascular B-cell lymphoma (IVLBCL) using nanopore sequencing combined with copy number variation (CNV) and DNA methylation analysis. This approach also effectively identified CSF-negative DLBCL and recurrent EBV-positive NK/T-cell lymphoma (NK/TCL).⁹⁰

Multimodal Imaging and Targeted Tracing Technologies

Multimodal imaging and targeted tracing technologies offer integrated solutions for in vivo precise localization and dynamic monitoring of lymphoma, complementing high-sensitivity in vitro diagnostics. In optical imaging, researchers developed sialic acid (SA)-modified OBADC-TPA-based second near-infrared (NIR-II) nanoparticles. These nanoparticles exhibited excellent biocompatibility and tumor accumulation, enabling photoacoustic (PA) and NIR-II fluorescence dual-mode imaging for high-contrast lesion localization.⁹¹ Using similar targeting strategies, chitosan-anti-CD20/CD19 antibody-fluorescent quantum dot nano-conjugates were designed to specifically bind CD19 and CD20 antigens overexpressed on NHL cells. This facilitated precise fluorescence imaging and identification.⁹²

To monitor lymphatic metastasis, researchers engineered an aminopeptidase N-activatable nanoprobe. This probe responds to aminopeptidase N overexpressed in the TME, generating strong PA and NIR-II fluorescence signals. This enables visualization of tumor lymphatic spread and guides surgical resection.⁹³ Notably, imaging applications now extend to advanced therapy monitoring. In cell therapy tracking, anti-CD5-conjugated lipid nanoparticles (LNPs) co-delivering CD19 CAR mRNA and prostate-specific membrane antigen (mPSMA) mRNA allowed non-invasive monitoring of in situ engineered CAR-T cell generation and tumor infiltration via 68Ga-PSMA-617 PET imaging.⁹⁴ For molecular target imaging, the [64Cu]Cu-NOTA-ABDB6 radiotracer demonstrated excellent tumor targeting and uptake in CD70-positive lymphoma models. This approach provided non-invasive, quantitative assessment of target expression using immunoPET.⁹⁵ Furthermore, a radiolabeled nanobody tracer targeting human CD8β enabled dynamic monitoring of CD8+ T-cell distribution and kinetics within the TME via SPECT/PET imaging. This provided crucial insights for immunotherapy response assessment.⁹⁶

Novel Immunosensing and Targeted Recognition Technologies

In vitro detection has benefited from novel immunosensing and targeted recognition technologies with high sensitivity and specificity for lymphoma. For example, researchers constructed an impedance immunosensor using a gold nanoparticle (AuNP)@DTSP-BA-modified glassy carbon electrode (GCE) with immobilized rituximab to detect lymphoma cells. This immunosensor achieved a linear detection range of 100–50,000 cells/mL and sensitivity of 64 cells/mL.⁹⁷ For ultrasensitive oncoprotein detection, an electrochemiluminescence (ECL)-electrochemical (EC) dual-mode immunosensor was developed for c-Myc (OPc-Myc), using AuNP-magnetic reduced graphene oxide (AuMrGO) as the immobilization platform and Tri-Ru as the signal label. With an indirect competition strategy, this sensor achieved detection limits of 4.9 pg/L (ECL mode) and 30 pg/L (EC mode) in patient blood samples.⁹⁸

Finally, novel targeting molecular tools are paving the way for diagnostic innovation. Researchers successfully employed artificial intelligence to design specific peptide binders and nanobodies targeting proliferating cell nuclear antigen (PCNA) and B-cell lymphoma 6 protein (BCL6). This laid the foundation for high-specificity detection tools.¹⁰⁶ Additionally, the thiol-dependent nanobody CB2 specifically recognizes unique surface thiol patterns on B-cell lymphoma cells. This recognition provides a novel molecular basis for lymphoma-targeted detection tools.¹⁰⁷

Advances and Discussion in Nanotechnology-Based Lymphoma Diagnosis

This section summarizes recent advances in nanotechnologies addressing core diagnostic challenges in lymphoma. These technologies include: First, EV-targeted detection, which enhances early diagnostic sensitivity by identifying specific chemical markers and physical characteristics; second, high-sensitivity nucleic acid biosensors, enabling precise detection of molecular biomarkers such as microRNA and cell-free DNA; third, multimodal imaging and targeted tracing technologies, overcoming limitations of traditional imaging by effectively identifying small lesions and monitoring treatment responses; fourth, novel immunosensing and targeted recognition platforms, providing highly specific tools for accurate in vitro detection. Collectively, these technologies support the evolution of lymphoma diagnostics toward non-invasive, real-time, and high-sensitivity approaches.

While their significant potential, clinical translation remains challenging. First, most technologies have been validated only in small cohorts and lack comprehensive evaluation in more complex patient populations, such as those with comorbidities or different lymphoma subtypes, affecting specificity and stability.¹⁰⁸ Second, certain imaging technologies are technically complex and require specialized equipment; moreover, large-scale production of nanoprobes is relatively costly, limiting adoption in primary healthcare institutions.^109,110 Finally, sample preparation methods for some detection technologies are tedious and involve strict storage and transportation conditions, restricting their applicability in routine clinical practice.¹¹¹

Application of Nanomedicine in Lymphoma Immunotherapy Treatment

Immunotherapies for lymphoma, including monoclonal antibodies, CAR-T-cell therapy, and cancer vaccines, have emerged as crucial therapeutic modalities following chemotherapy and radiotherapy.^112–115 However, clinical efficacy remains constrained by multiple challenges. Monoclonal antibodies encounter resistance due to target downregulation, such as loss of CD20 during rituximab treatment.¹¹⁶ CAR-T-cell therapy is limited by complex manufacturing processes, high costs, and frequent severe toxicities, including CRS and immune effector cell-associated neurotoxicity syndrome.^117–119 Conventional vaccines often fail to induce robust cellular immune responses, due to inefficient antigen uptake and presentation by dendritic cells.^120,121 Nanomedicine offers transformative strategies to overcome these limitations. Through rational design of nanoscale delivery systems, nanomedicine provides drug protection and targeted delivery, integrates multimodal therapies, and enables synergistic modulation of the TME. These advancements significantly enhance the efficacy and safety of lymphoma immunotherapy (Figure 2 and Table 2).

Figure 2 Nanomedicine Approaches for Lymphoma Immunotherapy Treatment. (A) Liposomal nanoparticles for drug delivery: Liposomal nanoparticles encapsulate both hydrophilic and hydrophobic drugs, as well as nucleic acids (DNA/RNA), enhancing their stability and facilitating targeted delivery to lymphoma cells through surface modifications, such as aptamers and receptor ligands. (B) Dendrimers for targeted gene delivery. Dendrimers are highly branched nanosystems capable of encapsulating drugs or genetic materials, achieving precise targeting and efficient delivery to lymphoma cells, thus overcoming barriers such as limited cellular uptake. (C) Inorganic nanoparticles for imaging and therapy. Inorganic nanoparticles, including iron oxide, mesoporous silica, and gold nanoparticles, are utilized for both diagnostic imaging and therapeutic applications. The blue arrows indicate the functional pathways of these nanoparticles toward non-invasive imaging modalities (CT and MRI) and their role as drug carriers in multimodal lymphoma treatment. (D) Iron oxide nanoparticles for magnetic thermotherapy. Iron oxide nanoparticles can serve as MRI contrast agents and, upon exposure to an external alternating magnetic field, generate localized heat for magnetic hyperthermia/thermotherapy. The blue arrows indicate the application flow from nanoparticle accumulation in lymphoma tissue to MRI imaging and subsequent magnetic thermotherapy treatment. Adapted from,55 Copyright © 2025 by the authors.

Table 2 Applications of Nanomedicine in Lymphoma Immunotherapy

Nanodelivery and Potentiation Strategies for mRNA Vaccines

Nanodelivery system innovations are pivotal to messenger RNA (mRNA) vaccine strategies. Conventional LNPs effectively encapsulate mRNA but inadvertently suppress translation due to type I interferon induction, thereby limiting antigen expression.^134,135 To address this, researchers developed multifunctional LNPs incorporating SitoC7A, replacing cholesterol with a sterol-STING agonist conjugate. The disulfide bond in SitoC7A enhances DC uptake and promotes endosomal escape, boosting mRNA translation. Concurrently, the C7A moiety selectively activates the STING pathway within DCs, enhancing DC maturation and antigen presentation while avoiding systemic interferon-mediated suppression.¹²² The spatiotemporal co-delivery of adjuvants is also crucial. Co-encapsulating ovalbumin-encoding mRNA with a palmitic acid-modified TLR7/8 agonist in lipid-polyethylene glycol nanoparticles formed “adjuvant-pulsed mRNA vaccine nanoparticles.” This strategy significantly enhanced antigen-presenting cell transfection efficiency, MHC class I antigen presentation, and induced potent protective and therapeutic anti-tumor immunity in lymphoma and prostate cancer models.¹²³ Similarly, co-loading unmodified mRNA with the TLR4 agonist MPLA into spleen-targeting LNPs doped with stearic acid elicited a robust Th1 immune response through synergistic immunostimulation. This approach effectively suppressed lymphoma growth and melanoma lung metastasis.¹²⁴ These studies highlight the versatility of nanocarriers in integrating mRNA delivery and immune modulation.

Nanotechnology Optimization of CAR-T-Cell Therapy

Nanotechnology also provides innovative strategies for improving CAR-T-cell therapy. Conventional CAR-T-cell production relies on viral transduction and ex vivo expansion, a labor-intensive process with risks due to permanent CAR expression.^136–138 To streamline this, researchers employed spleen-selective targeting LNPs for in situ generation of CAR-T cells. Intravenous injection of these LNPs efficiently delivered mRNA encoding Cre recombinase or a CD19 CAR to T cells in mouse spleens, inducing tumor regression and extending survival in a lymphocyte-rich B-cell lymphoma model.¹²⁵ Another study utilized anti-CD5-conjugated LNPs to co-deliver CD19 CAR mRNA and prostate-specific membrane antigen (PSMA) mRNA. This method achieved up to 75% disease-free survival in mice and innovatively employed 68Ga-PSMA-617 PET imaging for non-invasive tracking of in situ engineered, PSMA-labeled CAR-T cells. This approach provided dynamic evaluation of CAR-T-cell generation, tumor infiltration, efficacy, and toxicity.⁹⁴ For ex vivo CAR-T-cell engineering, an ionizable LNP platform delivered CAR mRNA to primary human T cells with efficiency comparable to electroporation but significantly reduced cytotoxicity. Thus, this method offers a safer alternative to viral vectors and electroporation.¹²⁶ Nanotechnology can also augment CAR-T-cell functions within the TME. To counteract TGF-β-mediated immunosuppression, researchers developed hydroxyethyl starch-polycaprolactone nanoparticles co-loaded with the TGF-β inhibitor LY2157299 and the photothermal agent indocyanine green. Mild photothermal effects accelerated inhibitor release within tumors, upregulated chemokines CXCL9/10/11 and receptor CXCR3, significantly promoting CAR-T-cell migration, tumor infiltration, and differentiation into an effector-memory phenotype. The combined therapy exhibited superior anti-tumor activity and recurrence suppression compared to CAR-T cells alone.¹²⁷

In addition, as an extension of nanomedicine, implantable scaffolds exhibit unique advantages for CAR-T cell therapy in lymphoma. Biodegradable implantable scaffolds can enhance the proliferation and antitumor efficacy of CAR-T cells while reducing systemic toxicity. These scaffolds function by constructing a physiomimetic immune microenvironment and modulating CAR-T cell phenotypes. For instance, the Drydux implantable CAR-T cell factory promotes sustained CAR-T cell release and differentiation into a memory phenotype in a murine systemic lymphoma model, inducing more durable tumor remission compared with conventional CAR-T therapy.¹³⁹ Similarly, the MASTER multifunctional alginate scaffold facilitates in situ generation of CAR-T cells. In lymphoma xenograft models, it exhibits superior cell expansion capacity and significantly enhances control over distant tumors.¹⁴⁰ Furthermore, the T cell-enhancing scaffold (TES) based on mesoporous silica rods, a nanoscale biodegradable subcutaneous implant, establishes a localized activation microenvironment via surface-integrated costimulatory ligands and soluble signaling molecules. In aggressive lymphoma murine models, this scaffold efficiently recruits and reactivates pre-infused CAR-T cells, significantly promoting their proliferation, intratumoral infiltration, and differentiation into a long-lived memory-like phenotype. Consequently, it significantly mitigates the risk of cytokine release syndrome (CRS) associated with systemic immune activation, providing superior antitumor efficacy and prolonged survival compared to conventional CAR-T therapy.¹⁴¹ Collectively, these studies demonstrate that implantable scaffolds constitute a novel technological platform for localized delivery and in vivo modulation of CAR-T cells, representing a promising strategy for enhancing both safety and effectiveness in lymphoma treatment.

Bispecific and Multi-Targeting Nanosystems

The development of bispecific and multi-targeting nanosystems provides opportunities to replicate and surpass functions of conventional bispecific antibodies. Bispecific T-cell engagers (BiTEs) show promise for B-cell lymphomas but face challenges such as short in vivo half-lives and complex production.^142–144 To overcome these limitations, researchers developed a bispecific nanosystem using a silica nanoplatform conjugated with antibodies targeting T cells or natural killer cells, and an effector antibody targeting B cells. This system simultaneously engages immune effector and lymphoma cells, facilitating artificial immune synapse formation, effectively activating cytotoxicity, and suppressing tumor proliferation.¹²⁸ Similarly, a novel FcγR1-expressing cell membrane-coated nanoparticle technology exploits high FcγR1 receptor expression to immobilize αCD3 and αCD20 antibodies through receptor-ligand interactions, creating bispecific nano-engagers with potent tumor-killing efficacy in vitro and in vivo.¹²⁹ For precision targeting in T-cell lymphoma, researchers fused nanobodies targeting CD30 and CD5 with granzyme B and displayed them on human ferritin nanoparticles via the Gv/Sd system, generating BiCD30/5-GF nanoparticles. This design achieved specific tumor targeting, while granzyme B multimerization enhanced apoptosis-inducing potency, significantly suppressing tumors and extending survival in mice.¹³⁰ Beyond engineered systems, understanding tumor-derived nanoparticles such as small extracellular vesicles (sEVs) is essential. Research revealed that sEVs derived from diffuse large B-cell lymphoma (DLBCL) carry CD20 comparable to parental cells. Activation of the TrkB pathway by neurotrophins further increased CD20 on sEVs, enhancing their ability to neutralize rituximab and protect tumor cells in in vitro and in vivo models. This discovery uncovers a novel resistance mechanism where tumor cells actively release “decoy” vesicles, highlighting the role of sEVs in immunotherapy resistance and identifying sEV CD20 levels as potential biomarkers for disease monitoring.¹⁴⁵

Nanomaterial-Mediated Remodeling of the Immune Microenvironment

Understanding the immunosuppressive mechanisms within the TME and leveraging nanotechnology for precise interventions are critical for improving therapeutic outcomes. Epigenetic dysregulation is a pivotal factor in lymphomagenesis.^146–148 Exploiting this, a “nanosonosensitizer” based on the UiO-66 metal-organic framework was developed. Upon ultrasound activation, this agent generates reactive oxygen species (ROS) that induce apoptosis, while simultaneously triggering autophagy-mediated inhibitor release. This process increases protein lipoylation and global mRNA methylation, thereby inducing “cuproptosis” and transcriptional suppression of PD-L1, respectively. This cascade synergistically induces immunogenic cell death and activates CD8+ T cells, effectively eliminating primary and metastatic lymphoma.¹³¹ To overcome Rituximab resistance, particularly in DLBCL characterized by PDK4 upregulation and CD20 downregulation, intelligent exosome nanoparticles (aCD20@ExoCTX/siPDK4) were engineered for the co-delivery of Rituximab and PDK4-targeted siRNA. This system reversed resistance mediated by the PDK4/HDAC8/CD20 pathway and exhibited synergistic therapeutic efficacy in a mouse model.¹³² Additionally, studies identified serum miR130b as a promoter of DLBCL progression by directly targeting the IFNAR1/p-STAT1 axis and recruiting immunosuppressive Th17 cells via OX40/OX40L interactions. Delivery of a miR130b antagonist via LNPs, or combination therapy with an OX40 agonistic antibody, significantly delayed tumor growth, highlighting novel microRNA-targeted immunotherapeutic strategies.¹³³ Furthermore, nanocarriers excel at the co-delivery of multiple immunomodulators. Intratumoral administration of immunomodulator combinations using biodegradable polymer nanoparticles substantially reshaped the immune cell landscape in both tumors and draining lymph nodes, enhancing long-term survival rates of therapeutic cancer vaccines to 75–100%.¹⁴⁹

Advances and Analysis of Nanotechnology-Optimized Lymphoma Immunotherapy

This section highlights four key areas where nanotechnology has significantly advanced lymphoma immunotherapy: (1) enhancing antigen presentation and immune activation of mRNA vaccines using novel nano-delivery platforms; (2) enabling in situ generation, functional enhancement, and non-invasive monitoring of CAR-T cells using nanocarriers; (3) developing bispecific/multitargeted nanosystems to overcome pharmacokinetic limitations associated with traditional bispecific antibodies; and (4) remodeling the TME with nanomaterials to reverse immunosuppression and improve immune therapy responses. These advancements provide promising directions to address current limitations in traditional immunotherapy, such as poor targeting, high toxicity, and drug resistance.

Current nano-immunotherapy platforms face multiple challenges in clinical translation.¹⁵⁰ Most studies rely on mouse syngeneic models or cell lines, whose immune microenvironment and heterogeneity differ significantly from human lymphoma, potentially causing discrepancies in clinical efficacy.¹⁵¹ Some nanosystems lack adequate biocompatibility data, and their long-term safety remains uncertain, with significant individual differences in therapeutic responses.^152,153 Additionally, large-scale production processes for nanocarriers have not been standardized. Complex nanosystems are challenging to manufacture at scale, and cost management remains difficult, limiting broader clinical application.¹⁵⁴

Nanomedicine in Gene Therapy and RNA Interference for Lymphoma

The pathogenesis and progression of lymphoma frequently involve aberrant expression of specific genes.^155,156 Conventional chemotherapy, due to its lack of specificity, often causes drug resistance and systemic toxicity. Conversely, gene therapy and RNA interference (RNAi) technologies targeting disease-initiating genes present promising alternatives. Delivering therapeutic nucleic acids, such as small interfering RNA (siRNA), enables precise oncogene silencing at the mRNA level, thereby suppressing tumors at their origin. However, clinical translation faces significant obstacles: unprotected nucleic acids degrade rapidly in serum, demonstrate poor cell membrane penetration, and predominantly accumulate within the endosomal-lysosomal pathway after internalization, limiting cytoplasmic delivery. This leads to reduced therapeutic efficiency and potential off-target effects.^157–159 Nano-delivery systems offer a pivotal solution to these limitations. Nanocarriers protect nucleic acids and can be functionalized for active targeting, enhancing lymphoma cell selectivity. Through sophisticated design, these systems facilitate cellular uptake and promote endosomal escape, ensuring efficient cytoplasmic delivery of therapeutic nucleic acids. Therefore, nanotechnology has become an essential platform for achieving precise and highly efficient gene regulation in lymphoma therapy (Table 3).

Table 3 Nanomedicine in Gene Therapy and RNA Interference for Lymphoma

Targeted siRNA Delivery and Silencing of Key Oncogenes

Efficient and cell-type-specific delivery of siRNA is essential for its therapeutic application. Researchers have developed versatile nanoplatforms with surface functionalization enabling precise targeting. For instance, a modular self-assembly platform utilizes interactions between membrane-anchored lipoproteins and the Fc region of antibodies. This design allows a single LNP formulation to deliver siRNA specifically to colonic macrophages or MCL cells by simply exchanging the conjugated antibody, effectively ameliorating inflammation and inducing tumor cell death in respective disease models.¹⁶⁰ Similarly, researchers engineered CD38-targeted LNPs to silence cyclin D1, which is overexpressed in MCL. These nanoparticles were selectively internalized by human MCL cells, effectively silenced cyclin D1 in vivo, and significantly prolonged survival in tumor-bearing mice.¹⁶¹ In T-cell acute lymphoblastic leukemia (T-ALL), PAMAM dendrimers modified with the sgc8 aptamer delivered BCL11B-targeted siRNA, selectively inhibiting T-ALL cell proliferation and promoting apoptosis, demonstrating strong therapeutic efficacy in animal models.¹⁶² For hard-to-transfect hematologic cancer cells, dual-targeted layer-by-layer nanoparticles, co-functionalized with a CD20 antibody and hyaluronic acid, markedly enhanced internalization by lymphoma and leukemia cells, efficiently downregulated Bcl-2 protein, and induced cancer cell apoptosis.¹⁶³ Furthermore, a triple-targeted, partially functionalized polymeric nanoparticle optimized the ratio of hyaluronic acid to antibodies, boosting siRNA delivery efficiency to NHL cells by nearly tenfold.¹⁶⁴ For aggressive lymphomas driven by multiple genetic factors, simultaneous silencing of several oncogenic targets can produce superior therapeutic outcomes.^46,171 In MCL, studies demonstrated that LNPs loaded with combined siRNAs targeting cyclin D1, Bcl-2, and Mcl-1 induced pronounced apoptosis and significantly inhibited tumor cell proliferation, achieving considerably greater efficacy compared to single-target strategies.⁴⁶ Moreover, aptamer-functionalized, protamine-based nanomedicines co-delivering chemotherapy drugs and ALK siRNA demonstrated precise combinational effects against anaplastic large cell lymphoma, effectively eliminating tumor cells with minimal off-target toxicity.²⁵

Combination Therapy: Nano-Co-Delivery of RNAi and Chemotherapeutic Drugs

Combining RNAi with chemotherapy holds significant promise for overcoming drug resistance and enhancing therapeutic outcomes through synergistic effects. Considerable research efforts are directed toward developing co-delivery nanocarriers. For example, covalent conjugation of doxorubicin to the surface of LNPs loaded with Bcl-2 siRNA facilitated effective Bcl-2 knockdown and nuclear delivery of doxorubicin in a Burkitt lymphoma model, resulting in synergistic tumor growth inhibition.¹⁶⁵ Several innovative nanoplatforms have been reported in anaplastic large cell lymphoma (ALCL). One aptamer-based nanomedicine integrated a CD30 aptamer, ALK siRNA, and doxorubicin via self-assembly, combining targeted chemotherapy with gene therapy. This approach significantly suppressed tumor growth with reduced side effects in animal models.¹⁶⁶ PH-responsive DNA nanomicelles co-loaded with doxorubicin and ALK siRNA were designed for intelligent payload release within the acidic TME. By silencing genes to enhance chemosensitivity, this system demonstrated remarkable synergistic anticancer activity both in vitro and in vivo.²³ Beyond siRNA, poly(L-histidine) nanoparticles co-delivered paclitaxel and a peptide nucleic acid targeting miR-155, significantly enhancing therapeutic efficacy in a lymphoma model without observed toxicity.¹⁶⁷

Targeting Non-Coding RNAs and Epigenetic Regulators

Targeting non-coding RNAs and epigenetic regulators, which play critical roles in lymphomagenesis, represents another promising therapeutic approach. In Kaposi’s sarcoma-associated herpesvirus-induced primary effusion lymphoma, carbon dots delivered locked nucleic acid inhibitors targeting viral miRNAs, effectively suppressing tumor cell proliferation and inducing apoptosis in vitro and in vivo, thereby validating the feasibility of targeting viral miRNAs.¹⁶⁸ In diffuse large B-cell lymphoma (DLBCL), miR-130b was identified as a promoter of progression through recruitment of immunosuppressive Th17 cells via the OX40/OX40L axis. Delivery of a miR-130b antagonist using LNPs effectively reversed this process and delayed tumor growth.¹³³ At the epigenetic level, studies revealed that transcription factor ZHX2 activates SLC3A2 via liquid-liquid phase separation, inhibiting ferroptosis in DLBCL. Disrupting this pathway using ZHX2-siRNA@LNP effectively suppressed tumors in vivo, identifying a novel therapeutic target and strategy for DLBCL.¹⁶⁹

Overcoming Drug Resistance and Innovative Action Mechanisms

Nanomedicine demonstrates considerable potential in overcoming drug resistance and pioneering novel therapeutic approaches. To address PDK4-mediated rituximab resistance in DLBCL, intelligent exosomal nanoparticles (aCD20@ExoCTX/siPDK4) were engineered for co-delivery of rituximab and siPDK4. By targeting the PDK4/HDAC8/CD20 signaling axis, this system restored CD20 expression, induced immunogenic cell death, and effectively reversed the immunosuppressive microenvironment in resistant models.¹³² Another innovative study developed a tumor-specific nanodomino-CRISPR system co-loaded with the photosensitizer Ce6 and a CRISPR/Cas9 plasmid targeting Bcl-2. This platform generated oxidative stress via photodynamic action and enabled precise Bcl-2 knockdown within tumor cells, simultaneously amplifying oxidative damage and activating the intrinsic apoptotic pathway. It effectively eliminated both superficial and deep-seated tumor cells, representing a spatiotemporally specific synergistic therapy.¹⁷⁰

Application and Issues in Nanotechnology-Based Lymphoma Gene Therapy

This section outlines core applications of nanotechnology in lymphoma gene therapy and RNA interference, including: (1) constructing targeted nano-delivery systems for precise silencing of key oncogenes; (2) developing combination platforms that co-deliver chemotherapy agents and RNA interference molecules, thus overcoming drug resistance through synergistic effects; (3) designing nanotherapeutic approaches targeting non-coding RNAs and epigenetic regulators, expanding gene therapy targets; and (4) innovating multi-gene silencing and intelligent responsive nanosystems to improve treatment precision and effectiveness. Nanocarriers have notably improved traditional limitations of nucleic acid therapeutics, such as rapid degradation, weak cellular uptake, and poor targeting.

However, gene therapy–related nanoplatforms face critical unresolved issues. Single-gene silencing strategies inadequately address the complexity of lymphoma driven by multiple genes, resulting in limited durability of therapeutic responses.^46,172,173 Some nanocarriers demonstrate insufficient stability in circulation, leading to rapid clearance and decreased delivery efficiency.¹⁷⁴ In addition, the synergistic mechanisms underlying certain combinational therapies remain unclear, complicating optimization of dosing ratios and treatment schedules.¹⁷⁵ Biosafety evaluations of nanocarriers require further improvement, particularly regarding risks from long-term accumulation. Finally, individualized delivery strategies tailored to diverse lymphoma subtypes remain undeveloped, failing to adequately meet varied clinical demands.^152,176

Theranostic Nanoplatforms: Innovative Technical Pathways for Precision Diagnosis and Treatment of Lymphoma

Although nanotechnology has significantly advanced diagnostic imaging and targeted lymphoma therapy, conventional approaches that separate diagnosis from treatment still face limitations in real-time efficacy assessment and dynamic treatment adaptation. Theranostic nanoplatforms have been developed to overcome these limitations. The core concept integrates specific targeting, highly sensitive imaging, and efficient therapeutic modules into a single nanosystem, enabling simultaneous disease diagnosis, therapeutic monitoring in vivo, and immediate intervention (Table 4). This section systematically outlines the design principles of such platforms. It begins by examining how targeted ligand modifications facilitate precise lesion localization, then explains how multimodal imaging enhances diagnostic accuracy and treatment monitoring, and finally discusses strategies for optimizing therapeutic outcomes through the synergistic integration of multiple treatment modalities, ultimately providing an innovative technical framework for comprehensive precision management of lymphoma (Figure 3).

Table 4 Nanotechnology-Based Theranostic Platforms for Lymphoma

Figure 3 Theranostic Nanoplatforms for Precision Diagnosis and Treatment of Lymphoma. This figure illustrates theranostic nanoplatforms that integrate diagnostic imaging and therapeutic functions for real-time monitoring and precise lymphoma management. Targeted ligands (indicated by arrows) enable accurate localization of lymphoma lesions, allowing highly sensitive imaging for disease detection and therapeutic evaluation. Photothermal therapy (PTT) and photodynamic therapy (PDT) integrated within a single nanoplatform, enhancing therapeutic efficacy through ROS-mediated cytotoxicity (shown by arrows) and thermal ablation (indicated by a heat symbol). Multimodal imaging modalities, including laser-based diagnostic approaches, enable real-time assessment of treatment responses. Additionally, the nanoplatform promotes vascular dilation (represented by expanding arrows) and enhances antitumor immunity by activating immune cells, such as dendritic cells (DCs), NK cells, and T cells (depicted by cell icons). Overall, this integrated theranostic strategy supports personalized lymphoma therapy, enabling precise monitoring, timely intervention, and dynamic adjustment of treatment regimens. Reproduced from,29 Copyright © 2024 by the authors.

Targeted Nanocarrier-Mediated Theranostics in Lymphoma

Targeted nanocarriers, characterized by their high drug-loading capacity, controlled-release properties, and tumor-targeting ability, have emerged as essential tools for lymphoma theranostics. By functionalizing nanomaterial surfaces with targeting moieties such as antibodies or small-molecule ligands, and incorporating imaging agents (eg, fluorescent probes, MRI contrast agents) alongside chemotherapeutic drugs, researchers have developed integrated nanosystems capable of simultaneous diagnosis and treatment. For instance, water-dispersible hybrid colloidal nano-immunoconjugates were fabricated by conjugating chitosan with anti-CD20, anti-CD19, or bispecific antibodies, and ZnS-based quantum dots. These conjugates specifically bind to CD19/CD20 receptors overexpressed on B-cell NHL cells, enabling fluorescence imaging and targeted cytotoxicity toward NHL while demonstrating minimal toxicity to normal cells. Their utility for ex vivo immunohistochemical diagnosis was further validated using patient-derived NHL tissue biopsies.⁹²

In the case of MYC/BCL6-positive double-hit DLBCL, a glutathione (GSH)-responsive nanoplatform was developed by co-loading lenalidomide (Len) and dexamethasone (Dex) onto upconversion nanoparticles (UCNPs) via GSH-cleavable linkers. The resulting UCNPs-Len-Dex system facilitated tumor monitoring through upconversion luminescence imaging, while also activating the CRBN E3 ligase to degrade IKZF1/3, thus suppressing DLBCL proliferation and maintaining immune microenvironment homeostasis. This platform exhibited excellent antitumor efficacy both in vitro and in vivo.¹⁷⁷ Additionally, rituximab (RTX)-modified Fe₃O₄ nanoprobes (Fe₃O₄-PEG-nAb) enhanced targeting of CD20-positive NHL cells through multivalent CD20 binding. The apoptotic effects induced by these probes were valence-dependent and further amplified by complement activation. In NHL xenograft models, the probes significantly reduced tumor burden and prolonged survival. Moreover, the intrinsic MRI properties of Fe₃O₄ enabled non-invasive monitoring of treatment efficacy.¹⁷⁸

Imaging-Guided Integrated CAR-T Cell Immunotherapy

Chimeric antigen receptor (CAR)-T cell therapy has demonstrated remarkable efficacy in hematologic malignancies; however, its clinical application in lymphoma is frequently limited by an immunosuppressive TME and insufficient CAR-T cell trafficking and infiltration. Theranostic strategies combining imaging with CAR-T cell regulation offer promising solutions to these challenges. One study developed an in situ CAR-T cell generation and tracking platform based on anti-CD5-conjugated LNPs. This system co-delivered CD19 CAR mRNA (mCAR19) and prostate-specific membrane antigen mRNA (mPSMA) as a tracking tag. Following pretreatment with interleukin-7 (IL-7) and repeated dosing, 75% of B-cell lymphoma-bearing mice achieved tumor-free survival. Using ⁶⁸Ga-PSMA-617 PET imaging, the generation and tumor infiltration of in situ-engineered PSMA-tagged CD19 CAR-T cells were non-invasively visualized.⁹⁴

To further enhance CAR-T cell infiltration into solid tumor-like NHL microenvironments, a folic acid (FA)-targeted nanoplatform loaded with gadolinium-integrated gap-enhanced Raman tags (Gd-GERT) and ibrutinib (FA-Gd-GERTs@Ibrutinib) was developed. This system enabled multimodal imaging (computed tomography/MRI/Raman). Its photothermal effects promoted angiogenesis, disrupted the extracellular matrix, and stimulated chemokine secretion within lymphoma tissues. Without compromising CD19 CAR-T cell activity, this approach significantly enhanced CAR-T cell infiltration into NHL models and demonstrated superior therapeutic outcomes when combined with CAR-T cell therapy.¹⁷⁹

Radionuclide-Labeled Theranostic Agents for Lymphoma

Radionuclide-labeled targeting agents, formed by conjugating radionuclides to antibodies or small-molecule ligands, enable simultaneous PET/SPECT imaging and radioimmunotherapy (RIT), representing a major category of lymphoma theranostics. For CD30-positive lymphoma, the anti-CD30 monoclonal antibody (IMB16) was conjugated to NOTA or DOTA chelators and labeled with ⁶⁴Cu or ¹⁷⁷Lu, generating [⁶⁴Cu]Cu-NOTA-IMB16 and [¹⁷⁷Lu]Lu-DOTA-IMB16, respectively. [⁶⁴Cu]Cu-NOTA-IMB16 exhibited tumor uptake of 19.2 ± 0.9%ID/g at 24 h in CD30-positive Karpas299 murine models, significantly higher than controls, allowing non-invasive evaluation of CD30 expression. Concurrently, [¹⁷⁷Lu]Lu-DOTA-IMB16 at a dose of 300 μCi demonstrated significantly stronger tumor growth inhibition compared with controls at 10 days post-injection, confirming its therapeutic potential.¹⁸⁰

For CD20-positive lymphoma, camelid single-domain antibody fragments (sdAbs), valued for their deep tumor penetration and favorable pharmacokinetics, were utilized. The sdAb 9079, selected for its high affinity toward hCD20, was labeled with ⁶⁸Ga for tumor-specific PET imaging with minimal off-target accumulation. When labeled with ¹⁷⁷Lu (¹⁷⁷Lu-DTPA-sdAb 9079), it achieved tumor uptake of 3.4 ± 1.3%ID/g at 1.5 h, exhibiting significantly higher tumor-to-blood and tumor-to-muscle ratios than ¹⁷⁷Lu-labeled rituximab. In murine models, it markedly prolonged median survival, demonstrating comparable efficacy to rituximab.¹⁸¹ Moreover, for CXCR4-positive lymphoma, an improved agent, [⁶⁸Ga/¹⁷⁷Lu]DOTA-r-a-ABA-CPCR4, was developed by optimizing linkers in PentixaFor and PentixaTher. This derivative exhibited approximately 10-fold higher affinity for hCXCR4 and a 4-fold increase in cellular uptake compared to its predecessors. The ¹⁷⁷Lu-labeled agent achieved tumor uptake of 18.3 ± 3.7%ID/g at 1 h in Daudi lymphoma models, demonstrating sustained retention over 48 h and minimal background accumulation, positioning it as a second-generation, high-performance CXCR4-targeted theranostic agent.¹⁸²

Progress and Analysis of Integrated Nanoplatforms for Lymphoma Diagnosis and Treatment

Focusing on the “diagnosis-treatment-monitoring” closed-loop framework, this section summarizes recent advances in integrated nanoplatforms for lymphoma management. These platforms include targeted nanocarrier-mediated fluorescence imaging-guided therapy, real-time efficacy monitoring and controlled drug release using upconversion nanoparticles, multimodal imaging-guided CAR-T cell therapy (MRI/PET), and radionuclide-labeled nanoprobes for targeted therapy and precise lesion tracing. Collectively, these approaches help bridge the gap between conventional diagnosis and treatment, providing a potential foundation for personalized precision management of lymphoma.

Despite these advantages, integrated theranostic nanoplatforms still face significant technical challenges. Some systems have complex architectures, resulting in cumbersome fabrication processes and poor batch-to-batch consistency, while multifunctional integration may compromise the original performance of individual components.¹⁸³ Several platforms rely mainly on passive targeting,¹⁸⁴ resulting in limited tumor-specific accumulation¹⁸⁵ and potential off-target deposition in normal tissues, which may cause adverse effects. In addition, high production costs and reliance on specialized imaging equipment limit their adoption in routine clinical practice.¹⁸⁶ Additionally, these platforms show limited adaptability to lymphoma heterogeneity, making it difficult to meet personalized treatment needs across different disease stages and lymphoma subtypes.^108,187

Challenges and Future Perspectives

Key Challenges in Clinical Translation of Nanomedicine

Although nanomedicine shows substantial potential for precise tumor diagnosis and treatment, its translation from basic research into clinical practice faces numerous challenges. First, the biosafety, long-term toxicity, and immunogenicity of nanomaterials are not fully understood, and their risks have been demonstrated in clinical trials. For example, the liposomal miR-34a mimic MRX34 was prematurely discontinued in a Phase I clinical trial due to severe immune-related adverse events in patients.¹⁸⁸ Second, standardized protocols for large-scale manufacturing and quality control of nanodrugs remain insufficient, and batch-to-batch variability directly affects clinical efficacy. Complex, multi-step preparation processes and the intricate physicochemical properties of nanomedicines further complicate consistency between batches. For instance, the paclitaxel polymeric micelle NK105, prepared from modified mPEG-b-P (Asp) block copolymers under laboratory conditions, achieved an encapsulation efficiency of approximately 23% and particle sizes around 90 nm. However, controlling the grafting ratio of the hydrophobic modifier 4-phenyl-1-butanol during large-scale production is challenging. This variability may cause fluctuations in encapsulation efficiency and particle size distribution, compromising therapeutic performance. In the Phase III clinical trial for metastatic/recurrent breast cancer, NK105 demonstrated an objective response rate (ORR) of 31.6%, lower than conventional paclitaxel formulations (39.0%). Additionally, its median progression-free survival (mPFS) did not meet the non-inferiority endpoint.^189–191

Finally, inherent limitations of preclinical models hinder accurate prediction of nanodrug therapeutic efficacy. The liposomal cytarabine-daunorubicin formulation (Vyxeos/CPX-351), a nanotherapeutic for high-risk acute myeloid leukemia (AML), extended overall survival (OS) from 5.95 months to 9.56 months in preclinical animal studies compared with standard chemotherapy, demonstrating notable tumor inhibition. Yet, this animal model did not adequately reflect the heterogeneous influence of common driver mutations in human leukemia, leading to clinical efficacy below preclinical predictions. Some patients even developed drug resistance and disease progression.¹⁹² Although patient-derived xenograft (PDX) models partially capture lymphoma genetic heterogeneity, they do not accurately represent drug distribution patterns within the human lymphatic system due to immunodeficient mouse hosts. Furthermore, serial passaging often leads to clonal selection,¹⁹³ increasing phenotypic divergence from the original tumor and further reducing reliability for clinical translation.

Future Advances in Lymphoma Nanomedicine

Looking ahead, breakthroughs in lymphoma nanomedicine will depend on deeper integration with advanced multidisciplinary fields. A pivotal direction involves the development of closed-loop theranostic systems. By integrating implantable microsensors and artificial intelligence algorithms, nanoplatforms could monitor tumor burden and microenvironmental changes in real-time, autonomously adjusting drug-release patterns for dynamic and precise control throughout the diagnostic-therapeutic continuum.^194–196 Concurrently, advances in single-cell technologies and spatial multi-omics offer new avenues for personalized nanomedicine,^197,198 facilitating patient-specific nanotheranostic strategies that precisely target distinct lymphoma subclones. In this context, AI-assisted protein design represents a particularly promising frontier. Deep learning-based methods can de novo generate miniaturized binding proteins specifically targeting lymphoma-associated antigens. Such protein modules may not only function as high-affinity targeting ligands for nanodrug functionalization but also undergo programmable self-assembly into structurally precise theranostic nanostructures.^199,200 Integration of synthetic biology with nanotechnology further expands these prospects. Coupling CRISPR-Cas systems with advanced nano-delivery platforms could enable in vivo gene correction and in situ reprogramming of immune cells, enhancing their tumor-homing capability and persistence.²⁰¹ From a translational perspective, combining biomimetic nanocarriers with advanced models such as organ-on-a-chip technology could establish more reliable drug screening platforms. Simultaneously, merging AI-driven protein design with nano-delivery systems promises a new generation of intelligent, bio-responsive nanomedicines.^202–206 For instance, by engineering protein switches cleavable by TME-specific enzymes to achieve on-demand drug release at the target site. The synergistic advancement of these cutting-edge technologies signals a transition for lymphoma nanomedicine from conventional material engineering toward an intelligent, personalized paradigm rooted in multidisciplinary integration.

Conclusion

Nanomedicine is progressively reshaping lymphoma diagnosis, therapy, and longitudinal disease monitoring by enabling high-sensitivity biomarker detection, improved molecular imaging, and targeted drug delivery with spatiotemporally controlled release. As summarized in this review, nanoplatforms improve drug bioavailability and accumulation in tumor and lymphoid tissues, support stimulus-responsive and combination therapeutic strategies to address disease heterogeneity and drug resistance, and enable theranostic integration that links treatment with real-time response evaluation, including potential applications in MRD surveillance. At the same time, successful clinical translation requires careful evaluation of key risks and practical barriers, such as long-term biosafety concerns (such as biodistribution, clearance, immunogenicity, and off-target organ accumulation), reproducible large-scale manufacturing and quality control, and interpatient biological variability, which may limit the effectiveness of single-target approaches. Looking ahead, priority research directions include the development of safety-by-design nanomaterials, standardized characterization methods and regulatory-aligned manufacturing pipelines, and intelligent nanosystems capable of dynamic sensing and adaptive drug release. Deeper integration with AI-assisted design, synthetic biology, and single-cell/spatial multi-omics technologies is expected to enhance patient stratification and personalize nanosystem selection, ultimately advancing safer, more effective precision management strategies for lymphoma.