Recent Advances in Novel Drug Delivery Systems for the Management of Cutaneous Squamous Cell Carcinoma

Introduction

Epidemiology

cSCC is a malignant skin tumor originating from squamous epithelial cells, accounting for approximately 20% of all skin cancers,¹ with an incidence second only to basal cell carcinoma. Over the past several decades, its global incidence has continued to rise,² particularly in regions such as Australia, the United States, and Europe, where the annual increase in new cases ranges from 3% to 8%.³ The disease predominantly affects middle-aged and elderly individuals, and its occurrence is closely associated with geographic factors; areas with intense ultraviolet radiation, such as low latitudes and high altitudes, exhibit higher incidence rates.⁴ In addition, individuals with immunosuppression (such as organ transplant recipients or patients with autoimmune diseases) and those with a history of long-term skin injuries, including burn scars or chronic ulcers, have a significantly higher risk of developing the disease compared with the general population.⁵ The continuous increase in the incidence of cSCC not only imposes a substantial burden of disease on patients but also poses new challenges for clinical management. Therefore, elucidating the pathogenesis of cSCC and developing more precise and effective therapeutic strategies have become major research priorities and urgent clinical needs in the field of cutaneous oncology.

Limitations of Conventional Treatment Regimens

At present, surgical excision remains the primary approach in the clinical management of cSCC.⁶ For patients with low-risk early lesions or those who are not suitable candidates for surgery, local treatment modalities such as radiotherapy or cryotherapy may be considered to control disease progression. In contrast, for patients whose disease has advanced to a locally advanced stage or has metastasized, systemic therapy is commonly employed in clinical practice,⁷ including chemotherapeutic agents such as cisplatin and 5-fluorouracil (5-FU), or targeted therapy with epidermal growth factor receptor (EGFR) inhibitors. However, conventional therapeutic approaches, including surgery, radiotherapy, chemotherapy, and photodynamic therapy, present notable clinical limitations. Patients with multiple lesions or poor surgical tolerance often cannot endure surgical treatment, radiotherapy is associated with severe skin toxicity,⁸ and systemic chemotherapy exhibits nonspecific distribution, making it difficult to achieve precise accumulation at tumor sites, which frequently leads to systemic adverse reactions such as bone marrow suppression, nephrotoxicity, ototoxicity, and gastrointestinal responses.⁹ These unmet clinical needs have driven the development of novel drug delivery systems for cSCC. In addition, the pronounced tumor heterogeneity of cSCC, the inherently poor solubility and low bioavailability of chemotherapeutic agents, and the emergence of multidrug resistance (MDR) during treatment further limit the clinical efficacy of chemotherapy.¹⁰ Similarly, although targeted therapies can act precisely on tumor-specific driver pathways, long-term administration tends to induce resistance mutations and compensatory activation of signaling pathways, resulting in comparable efficacy bottlenecks. These unmet clinical needs have driven the development of novel drug delivery systems for cSCC and have become the core motivation for developing new therapeutic strategies.¹¹

Advantages of Emerging Therapeutic Strategies

To overcome the clinical limitations of conventional therapies for cSCC, nanotechnology-based drug delivery systems have demonstrated significant application potential. Strategies such as constructing core–shell or vesicular structures, modifying tumor-homing ligands, and regulating particle size to optimize the enhanced permeability and retention (EPR) effect enable the co-loading and targeted delivery of chemotherapeutic agents, nucleic acids, and photosensitizers to tumor sites.¹² These approaches not only improve the local bioavailability of drugs and enhance antitumor efficacy but also effectively reduce nonspecific drug distribution in normal tissues, thereby mitigating the systemic toxic side effects associated with conventional cSCC treatments.¹³ Such technologies exhibit remarkable therapeutic advantages and are highly consistent with the requirements of precision therapy for cSCC.^14,15 These novel drug delivery carrier materials, including but not limited to liposomes, polymeric nanoparticles, and microneedles, exhibit broad therapeutic advantages owing to their unique structures and functions.¹⁶ Notably, these advanced delivery systems have demonstrated remarkable efficacy and safety in multiple in vitro and in vivo studies, providing a feasible technological approach to overcoming therapeutic bottlenecks in cSCC and showing great potential for clinical translation.^14,15

Purpose and Scope of the Review

Based on this, the present review aims to comprehensively analyze recent advances in novel drug delivery systems for cSCC treatment (Figure 1). It focuses on elucidating the structural characteristics and functional advantages of carrier materials such as nanocarrier technologies, cell-penetrating peptide modification strategies, and DNA–metal composite materials; examining the mechanisms of action and application outcomes of novel drug delivery methods including microneedle arrays and hyaluronic acid-based carriers; and evaluating the potential of these innovative delivery systems in advanced therapy strategies. Furthermore, the review discusses their current status in clinical translation, key challenges, and future development directions, with the goal of providing a solid theoretical foundation and forward-looking perspective to promote the development and clinical application of novel drug delivery systems, thereby advancing cSCC therapy toward greater efficiency, safety, and precision.

Figure 1 Schematic representation of nanomedicine strategies for cutaneous squamous cell carcinoma (cSCC). Abbreviations: DOX, doxorubicin; ICI, immune checkpoint inhibitor. Notes: This figure divides cSCC nanotherapies into three core modules: the upper section presents conventional nanocarriers (liposomes, polymeric micelles, gold nanoparticles, metal-organic frameworks) for targeted drug delivery; the left section illustrates novel local delivery systems (hyaluronic acid carriers, microneedle arrays, hydrogels) for enhanced skin penetration; and the right section outlines combination therapy strategies (tumor microenvironment modulation, nanoparticle-mediated ICI delivery, phototherapy synergy) to boost antitumor efficacy.

Search Strategy

This review was conducted in strict accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA 2020) guidelines to ensure the rigor and transparency of the literature selection and analysis process. Relevant studies were retrieved from four major electronic databases—PubMed, Web of Science, Embase, and CNKI—from their inception to March 2026. To balance timeliness and academic traceability, the search primarily focused on innovative studies published in the past 15 years (2011–2026), while also including earlier milestone basic research. Search terms combined Medical Subject Headings (MeSH) and free-text keywords, including “cutaneous squamous cell carcinoma,” “cSCC,” “drug delivery system,” “nanocarrier,” “microneedle,” “hyaluronic acid carrier,” “immune checkpoint inhibitor,” “phototherapy,” and “tumor microenvironment modulation.” The search strategy was constructed using Boolean operators (AND, OR, NOT) based on the research themes. The literature screening process was conducted in accordance with the PRISMA 2020 flow diagram. First, EndNote 2025 software was used to remove duplicate records based on matching criteria including title, author, journal, and year of publication. Second, two independent researchers screened titles and abstracts to exclude irrelevant studies. Third, potentially eligible articles were subjected to full-text assessment. Finally, any discrepancies were resolved through discussion with a third independent researcher. A structured quality assessment method was applied to all included studies to ensure that only medium- to high-quality literature was incorporated into the final synthesis and analysis.

Pathogenesis and Clinical Characteristics

Core Pathogenic Factors

The primary cause of cSCC is prolonged exposure to ultraviolet radiation (UVR).¹⁷ UVR directly induces characteristic DNA injuries in keratinocytes, primarily forming cyclobutane pyrimidine dimers (CPDs) and 6-4 photoproducts (6-4PPs).¹⁸ If these injuries are not promptly repaired, they will drive specific genetic mutations, among which the TP53 tumor suppression gene is the most common mutational target in cSCC, with a mutation rate as high as 50%–90%. Most of these mutations are missense mutations occurring in the DNA-binding domain, directly impairing the ability of the p53 protein to recognize and bind to the DNA of target genes,¹⁹ thereby losing its core functions of initiating cell cycle arrest, promoting DNA repair, and inducing apoptosis. The functional inactivation of TP53 disrupts normal cellular regulatory mechanisms, ultimately leading to uncontrolled abnormal proliferation of keratinocytes and driving the initiation and progression of cSCC.²⁰ Other risk factors include exposure to ionizing radiation, burn scars, and chronic ulcers.

Clinical Progression and Characteristics

The clinical manifestations of cSCC are also of great significance, as its development is a progressive process rather than a sudden occurrence. It can be divided into three stages (Figure 2): transformation of normal epidermal keratinocytes, precursor lesion, and invasive carcinoma.²¹ Most cSCCs originate from certain precursor or in situ lesions, with actinic keratosis (AK) and Bowen’s disease (BD) being the most common.²² Bowen’s disease is an intraepidermal squamous cell carcinoma in situ, in which the lesion is confined to the epidermis and does not breach the basement membrane zone.²³ Its typical clinical presentation is a well-demarcated erythematous scaly plaque on the skin or mucosal surface. If left untreated for a prolonged period, there is an approximately 3–5% risk of progression to invasive cSCC, and in some cases, distant metastasis may occur.²⁴ When the lesion progresses to invasive cSCC, the symptoms usually manifest as a persistently enlarging mass or ulcer, which may be accompanied by crusting, bleeding, or exudation.²⁵ In addition, some cases of invasive cSCC exhibit an aggressive growth pattern, with a high propensity for local recurrence, regional lymph node metastasis, and even distant metastasis. The efficacy of conventional treatment regimens for such cases is limited, and the prognosis is poor.²⁶ It is noteworthy that individuals with immunosuppression, such as organ transplant recipients, have a higher risk of cSCC recurrence and metastasis and a worse prognosis.²⁷ This further underscores the urgency of developing new effective therapeutic strategies.

Figure 2 Multistage Progression of Cutaneous Squamous Cell Carcinoma (cSCC). Notes: (a) Under the influence of major risk factors such as chronic ultraviolet radiation (UVR), normal skin accumulates DNA damage (eg, TP53 gene mutation), which in turn drives the malignant transformation of keratinocytes. (b) Premalignant Lesion Stage: This stage includes reversible actinic keratosis and intraepidermally confined Bowen’s disease. (c) Invasive cSCC Stage: Tumor cells breach the basement membrane and infiltrate into the deep layers, while acquiring the potential for local recurrence and lymph node metastasis.

Nanocarrier and Functional Biomaterial Platforms for Targeted cSCC Therapy

The advancement of drug delivery materials is profoundly transforming the treatment of cSCC. Nanocarrier technologies represented by liposomes, polymeric nanocarriers, and inorganic nanoparticles have markedly improved drug bioavailability and targeting capability through precise delivery and multifunctional integration,²⁸ thereby enhancing antitumor efficacy while reducing toxic side effects. Meanwhile, cell-penetrating peptide (CPP) modification technology, leveraging its superior permeability and targeting modification capacity, effectively enhances the tissue permeability of nanocarriers and the uptake rate by tumor cells, offering an efficient and low-toxicity strategy for the local treatment of cSCC. In addition, DNA–nanocomposite materials integrate the programmable recognition capability of DNA with the physicochemical properties of inorganic or polymeric materials, offering the potential to overcome challenges in skin cancer treatment such as poor targeting, hypoxic microenvironments, and multidrug resistance,²⁹ thereby providing a new approach for noninvasive precision therapy. This strategy achieves a favorable balance between enhanced efficacy and reduced toxicity through precise integration of material functions, demonstrating significant potential for clinical translation.

Nanocarrier Technology

Liposomes

As an emerging technology, nanocarrier technology has introduced new breakthroughs in the treatment of cSCC. It has been validated in inflammatory, infectious, and pigmentary diseases through targeted delivery, controlled release, and barrier penetration.³⁰ These core advantages align with the therapeutic needs of cSCC, making nanocarriers a promising candidate.³¹ The first nanoparticle applied in medicine was the liposome, developed nearly 50 years ago.³² As a closed vesicular structure, liposomes have demonstrated great potential in the field of messenger RNA (mRNA) delivery.³³

mRNA-based therapeutic strategies hold unique value in cSCC, as they can achieve molecularly targeted therapy by regulating key pathogenic genes such as mutant TP53,³⁴ and can also encode drug resistance–related silencing sequences to reverse chemotherapy resistance.³⁵ However, free mRNA faces multiple obstacles in application, it is easily degraded by nucleases in the skin microenvironment and systemic circulation,³⁶ its electronegativity limits penetration through the stratum corneum barrier, and it lacks active targeting capability toward cSCC cells, which readily leads to off-target effects.¹¹ Therefore, nanocarrier-mediated delivery is indispensable for the clinical application of mRNA in cSCC.

Liposomes form stable complexes with negatively charged mRNA through cationic modification, which not only effectively protects mRNA from nuclease degradation but also enables cell fusion or endocytosis-mediated intracellular delivery via the phospholipid bilayer structure.³⁷ This process markedly enhances the targeting specificity and cellular penetration of mRNA, ultimately achieving effective drug accumulation in the target organ and substantially increasing the local drug concentration at the lesion site. This targeted delivery strategy can significantly reduce systemic adverse reactions while enhancing therapeutic efficacy.³⁷ In addition, liposomes are primarily composed of endogenous substances and possess a structure highly similar to that of biological cell membranes, conferring excellent biocompatibility.³⁸ Given these advantages, liposomes have become an important drug delivery vector in the treatment of cSCC and are playing an increasingly significant role in targeted therapy. However, the intrinsic structure of liposomes still presents certain limitations. Their physicochemical stability is relatively poor, and during storage, phospholipid oxidation, hydrolysis, and vesicle aggregation may occur, leading to drug leakage from the encapsulated core.³⁹ In addition, conventional liposomes are rapidly cleared by the reticuloendothelial system in vivo. Although PEGylation can prolong their half-life, the resulting accelerated blood clearance effect may compromise the efficacy of repeated administration. Furthermore, liposomes generally exhibit a relatively low drug loading capacity, particularly with insufficient encapsulation efficiency for hydrophilic drugs, and quality control during large-scale production remains challenging.⁴⁰ These factors collectively restrict the broad clinical application of liposomes in cSCC therapy and have prompted researchers to explore polymer-based nanocarriers with more tunable physicochemical properties.

Polymeric Nanocarriers

Given the limitations of liposomes in terms of stability and drug loading capacity, polymer-based nanocarriers exhibit superior applicability due to the high tunability of their chemical structures and physical properties.⁴¹ These materials possess biodegradability, biocompatibility, and good storage stability, and are widely used in the field of drug delivery, showing unique potential in reversing cSCC drug resistance. Commonly used polymers, such as poly(lactic-co-glycolic acid) (PLGA), polylactic acid (PLA), and polycaprolactone (PCL), all demonstrate excellent biocompatibility and degradability, and their surfaces can be chemically or physically modified to achieve targeted delivery.

In skin cancer animal models, following intravenous injection or local administration, octa-functionalized PLGA nanoparticles achieve efficient accumulation at the lesion site through the synergistic effects of passive and active targeting, thereby significantly reducing toxic and side effects on normal tissues.⁴² Experimental results indicate that this delivery system markedly reduces tumor volume and prolongs animal survival time. Moreover, due to the biodegradability of PLGA, it does not induce a significant inflammatory response or organ injuries, demonstrating promising potential for clinical application.⁴³

In addition to the conventional polymer nanoparticles mentioned above, several types of polymer vectors with unique structures or functions have also attracted considerable attention. Polymeric micelles are formed by the self-assembly of amphiphilic block copolymers. Their hydrophobic core can effectively solubilize poorly soluble drugs, while the hydrophilic shell confers prolonged circulation capability. In addition, their small particle size enables passive tumor targeting through the EPR effect.⁴⁴ Such micelles have demonstrated unique value in the treatment of cSCC. pH-sensitive polyhistidine–PEG block copolymer micelles can respond to the acidic tumor microenvironment, where protonation of imidazole groups triggers micelle disassembly and rapid drug release. This targeted release behavior theoretically helps reduce toxic side effects on normal skin tissues and offers superior biosafety potential compared with conventional non-pH-sensitive micelles.⁴⁵ Morita M et al modified pH-sensitive micelles with EGFR antibodies, achieving dual targeting through the combined action of the EPR effect and receptor-mediated endocytosis, which resulted in significantly enhanced accumulation efficiency in tumor tissues compared with non-targeted micelles.⁴⁶ However, micelles still face core challenges: they are prone to dissociation and premature drug release in systemic circulation due to dilution and serum protein adsorption, and their insufficient stability severely limits clinical translation. In addition, issues such as low endolysosomal escape efficiency and batch-to-batch variation during large-scale production remain to be addressed.⁴⁷ Optimization strategies include introducing disulfide cross-linking within the core, modifying with cell-penetrating peptides, and employing microfluidic technologies.⁴⁵

Dendrimers possess a highly branched three-dimensional architecture and precise molecular weight, with surface functional groups capable of simultaneously conjugating targeting ligands, imaging agents, and multiple drugs, thereby enabling the construction of multifunctional delivery platforms.⁴⁸ In the treatment of cSCC, studies have utilized poly(amidoamine) (PAMAM) dendrimers for methotrexate delivery, demonstrating significant antitumor efficacy in cSCC animal models.⁴⁹ Other research teams have achieved active targeting through EGFR antibody modification, which has been shown to enable specific accumulation in tumors with high EGFR expression.⁵⁰ Moreover, dendrimers can serve as siRNA delivery vectors, and dual-targeted dendrimer-based delivery systems have achieved efficient gene silencing in tumor cells. This strategy provides a novel vector concept for gene therapy of cSCC.⁵¹ However, its synthesis process is complex and costly, and the unmodified surface cationic groups tend to induce charge-related toxicity.⁴⁸ In addition, the mechanisms of in vivo degradation and metabolism have not been fully elucidated, which limits its potential for clinical translation.

Molecularly imprinted nanoparticles (MINPs) are functionalized nanocarriers with a polymer-based framework. Through template elution technology, specific recognition sites complementary to the target molecules in size, shape, and chemical functional groups are constructed on the surface or within the particles.⁵² Compared with biological antibodies, MINPs offer advantages such as lower cost and higher stability,⁵³ demonstrating unique application potential in targeted delivery and tumor biomarker detection for cSCC.⁵⁴ Current studies on MINPs in the field of cSCC have achieved certain progress. It has been shown that MINPs targeting the intracellular epitopes of EGFR can be prepared using molecular imprinting technology. These carriers are capable of specific recognition and activity regulation of EGFR, acting only on tumor cells with high EGFR expression, while exhibiting significantly lower toxicity toward normal cells than conventional chemotherapeutic drugs.⁵⁵ However, the clinical translation of MINPs still faces challenges,⁵⁶ primarily due to the difficulty of completely removing template molecules in the complex in vivo environment and the difficulty in maintaining the stability and selectivity of the recognition cavities. Although improvement strategies such as surface modification and novel elution techniques have been developed, further refinement is required to advance their clinical application.

Inorganic Nanoparticles

In addition to organic nanocarriers, inorganic nanoparticles, owing to their unique physicochemical properties, provide another important platform for the treatment of cSCC. Common types include mesoporous silica, gold, silver, platinum, copper oxide, titanium dioxide, and cerium oxide nanoparticles.

Gold nanoparticles (AuNPs) have demonstrated diverse application strategies in the treatment of cSCC. Zheng et al developed a spherical nucleic acid (SNA) platform based on gold nanoparticles, which successfully achieved localized transdermal delivery of small interfering RNA (siRNA) and effectively inhibited tumor growth in a cSCC model.⁵⁷ Compared with the conventional strategy of administering AuNPs after in vitro synthesis, Ipanjan Pan et al proposed a disruptive paradigm in which gold ion precursors and a cell-penetrating peptide were locally injected, allowing the highly reductive environment within tumor cells to in situ reduce the gold ions into photothermally active gold nanoparticles. This approach enables on-demand synthesis and accumulation of therapeutic agents at the target site, avoiding issues such as aggregation of in vitro synthesized gold nanoparticles, poor in vivo stability, and insufficient targeting, thereby expanding the application scope of gold nanomaterials in tumor therapy.⁵⁸

Silver nanoparticles (AgNPs) also exhibit unique application value. Daniel et al developed an AgNP-based intelligent nanoplatform that enables precise control of microRNA-148b release under UVR. The delivered miR-148b directly targets and inhibits key nodes of the Ras signaling pathway, thereby blocking the malignant transformation and proliferation of cancer cells at the source. In a Ras-induced cSCC transgenic mouse model, localized light irradiation triggered the precise release of miRNA, leading to tumor regression through the induction of apoptosis and modulation of inflammation. This study demonstrates the great potential of silver nanoparticles in constructing spatiotemporally controllable intelligent gene therapeutics and provides a new strategy for local gene therapy of cSCC.⁵⁹

As summarized in Table 1, the continuous development of nanoplatforms such as liposomes, polymeric nanocarriers, and inorganic nanoparticles provides diversified solutions for improving the therapeutic efficacy and safety of cSCC by enhancing drug targeting, biocompatibility, and intelligent controlled release capabilities, demonstrating a clear prospect for clinical translation.

Table 1 Classification, Characteristics, Advantages, Disadvantages, Examples, and Research Outcomes of Major Nanocarriers in Cutaneous Squamous Cell Carcinoma (cSCC) Therapy

Cell-Penetrating Peptide Modification Technology

Cell-penetrating peptides (CPPs) are short peptides capable of efficiently traversing cell membranes or tissue barriers.⁶⁰ In recent years, they have been widely employed to mediate the delivery of biomolecules such as nucleic acids and chemotherapeutic drugs.⁶¹ Their delivery process does not require receptor mediation and does not cause significant damage to the cell membrane. In addition, CPPs possess several advantageous characteristics, including high specificity, small molecular size, ease of modification, and excellent biocompatibility.⁶² Owing to these advantages, CPPs have attracted considerable attention in the fields of local⁶³ and transdermal targeted drug delivery and have become one of the core technologies for overcoming the skin barrier and enhancing targeting in the local treatment of cSCC. At present, the application of CPPs in cSCC therapy mainly focuses on the following two directions.^64,65

In enhancing transdermal delivery, CPPs can effectively overcome the stratum corneum barrier of the skin, enabling local drugs to reach therapeutically effective concentrations. Li et al developed a CPP-modified cationic delivery gel (LR@DTFs-CPP gel) loaded with a lycorine–oleate ion complex (LR-OA) for the topical treatment of cSCC. In an A431 cSCC xenograft mouse model, topical application of this gel reduced tumor volume by approximately 75% compared with the saline control group (p < 0.01), while the mice maintained stable body weight, exhibited normal hematological parameters, and showed no organ lesions in tissue sections.⁶⁶ These findings demonstrate that the therapeutic efficacy was confined to the tumor site without systemic adverse reactions, providing an efficient and low-toxicity local treatment strategy for topical targeted drug delivery in cSCC.

In enhancing the intracellular delivery efficiency of nanocarriers, CPPs have emerged as a key tool for addressing the imbalance between targeting specificity and penetration capacity in traditional vectors, owing to their efficient transmembrane capability and modifiability. Gan et al employed a subtractive biopanning strategy to screen a phage display peptide pool and identified a CPP (sequence: NRPDSAQFWLHH) with high specificity for human squamous cell carcinoma A431 cells. Mechanistic studies revealed that this peptide specifically binds to the EGFR, which is highly expressed on the surface of skin cancer cells, and enters tumor cells through a clathrin-mediated endocytic pathway (Figure 3). Moreover, it shows no targeting affinity toward normal skin cells, effectively overcoming the off-target limitations of conventional targeting molecules. Further research utilized a nanoglue technique to conjugate this CPP onto the surface of virus-like nanoparticles, achieving precise vector delivery and providing a novel specific ligand and a feasible technical approach for skin cancer-targeted drug delivery systems.⁶⁵

Figure 3 Illustrates the complete screening and delivery workflow of the “EGFR-targeting cell-penetrating peptide (CPP)” in the precision therapy of cSCC. Notes: (A) Through a phage display library, “negative selection (excluding peptides binding to normal keratinocytes)” followed by “positive selection (enriching peptides binding to A431 cSCC cells that overexpress EGFR)” was performed to obtain an EGFR-specific CPP (sequence: NRPDSAQFWLHH). (B) This CPP was conjugated to truncated hepatitis B core antigen (HBcAg) virus-like particles (VLPs) via a “nanogel” linkage to construct a “CPP-VLP complex.” The resulting complex specifically binds to A431 cSCC cells without affinity for normal cells and enters cancer cells through clathrin-mediated endocytosis, thereby achieving precise intracellular delivery. This strategy provides an efficient carrier platform for targeted therapy of cSCC.

DNA Nanotechnology

In recent years, DNA nanotechnology has demonstrated unique advantages in the precise treatment of cSCC due to its programmable assembly properties and high molecular recognition capability.²⁹

In the development of novel delivery vectors, the research group led by Li Lele, inspired by metal–organic coordination chemistry, established a new method for the self-assembly of synthetic DNA nanostructures through metal coordination interactions, successfully constructing metal–DNA nanostructures. These structures achieved efficient nucleic acid delivery at both cellular and in vivo levels, overcoming the traditional trade-off between delivery efficiency and biocompatibility. Both in vitro and in vivo experiments confirmed their excellent tumor recognition ability and antitumor activity,⁶⁷ which were attributed to the synergistic effects of structural stability and precise molecular targeting, thereby opening a new avenue for the construction of DNA nanostructures.

In the design of intelligent responsive systems, the team led by H.A. developed a targeted DNA nanomachine based on a tetrahedral DNA framework. This complex can specifically respond to miRNA signals within tumor cells, triggering a cascade reaction that amplifies singlet oxygen generation, thereby achieving precise and efficient treatment of cSCC. Animal experiments demonstrated that this system effectively ablated cSCC tumors in experimental mice, with negligible systemic toxicity and inflammatory response.¹¹ These findings expand the application boundaries of DNA complexes in noninvasive skin tumor therapy and provide important theoretical and technical insights for the design of subsequent skin-related tumor-targeted nanomedicines.

In the development of in situ assembly materials, Zhang et al used spherical nucleic acids (SNAs) as fundamental units and employed the programmability of DNA hybridization to construct DNA–metal condensates with liquid metamaterial properties through programmed self-assembly. This breakthrough not only enriches the morphological library of DNA materials but also establishes a materials foundation for the in situ construction and on-demand programming of localized drug delivery systems at skin lesions.⁶⁸ In addition, precisely self-assembled structures composed entirely of DNA, such as DNA origami, provide unique platforms for drug delivery, demonstrating the diversity of DNA nanotechnology.²⁹

These studies collectively highlight, from different perspectives, the critical value of DNA nanotechnology in enhancing therapeutic targeting, enabling intelligent responses, and constructing novel materials, thereby laying a solid foundation for its clinical translation in the precise treatment of cSCC.

Advances in Local Targeted Drug Delivery Systems for cSCC

In recent years, significant progress has been made in the development of local drug delivery systems for cSCC. Among these, three delivery strategies—microneedle arrays (MNs), hyaluronic acid (HA)-based vectors, and hydrogels—have attracted extensive attention due to their unique advantages. Microneedle arrays enable efficient transdermal delivery by creating transient microchannels⁶⁹ and offer the benefits of being minimally invasive and painless.^70,71 Hyaluronic acid enhances drug accumulation through CD44 receptor-mediated active targeting.⁷² Hydrogels serve as drug reservoirs to achieve sustained and controlled release. Collectively, these three technologies overcome the limitations of low transdermal efficiency and insufficient targeting in conventional cSCC therapies, providing critical technical support for precise and efficient local treatment.

Microneedle Array

Multifunctional Composite Microneedle Patches

As a minimally invasive transdermal drug delivery platform, MNs rely on micron-scale needle tips (150–1500 µm in length) to penetrate the physical barrier. These tips are designed to pierce only the epidermis, creating transient and self-healing microchannels. This design bypasses the stratum corneum lipid barrier, enabling the direct delivery of drugs or nanocarriers into cSCC lesions located in the epidermis and dermis, while ensuring a painless and minimally invasive process. This approach effectively overcomes the low transdermal efficiency of conventional topical therapies and has become a research focus for localized cSCC treatment.⁷³ Huang et al developed a self-heating microneedle patch in which the needle tips were loaded with PLGA for the sustained release of thymoquinone (TQ), the base layer was loaded with 5-FU, and the backing layer generated heat through iron powder oxidation to promote drug permeation. This design significantly increased the drug concentration at the tumor site and the tumor suppression rate, demonstrating high efficacy, low side effects, and sustained inhibition of tumor recurrence in cSCC animal models.⁷⁴

Intelligent Collaborative Microneedle Systems

In the field of intelligent synergistic therapy, Xue et al developed a wearable flexible ultrasonic microneedle patch (wf-UMP) that integrates dissolvable microneedles with a flexible ultrasonic transducer. Through piezocatalytic therapy (PCT), this patch generates reactive oxygen species (ROS) and works synergistically with immune checkpoint inhibitors to achieve efficient treatment and immune regulation of both primary and distant tumors in mouse models. In vivo and in vitro experiments demonstrated that this system effectively inhibited tumor growth, significantly prolonged the survival of tumor-bearing mice, and exhibited good biosafety.⁷⁵ This technology features simple operation and high patient compliance, providing a new strategy for minimally invasive and precise treatment of superficial tumors such as cSCC, and promoting the clinical translation of microneedle arrays in tumor immunotherapy.

Dissolving Microneedles for Photodynamic Therapy

Dissolvable microneedles represent an important direction in the development of microneedle technology. Although conventional microneedles can penetrate the skin barrier,⁷⁶ they are limited by shallow penetration depth and uneven drug distribution. In contrast, dissolvable microneedles can rapidly dissolve within the skin, enabling efficient drug release.⁷⁷ Hou et al developed Ulvan-based dissolvable microneedles loaded with ALA–catalase–PLGA nanoparticles (ACP-U). These microneedles rapidly dissolved within 4–5 minutes after application, efficiently releasing ACP nanoparticles into tumor tissues and effectively overcoming the bottleneck of the low transdermal efficiency of free ALA. Experimental results demonstrated that ACP-U microneedles exhibited no significant cytotoxicity and caused no adverse effects on mouse body weight, routine blood parameters, hepatic and renal function, or major organs. The micropores formed after microneedle application healed rapidly within 20 minutes, indicating good minimal invasiveness and safety. In addition, this delivery system significantly enhanced the photodynamic therapeutic efficacy against cSCC by improving the hypoxic tumor microenvironment, demonstrating considerable potential for clinical translation.⁷⁸

Hyaluronic Acid-Based Carriers

HA is a natural biomacromolecule with multifunctional roles in tissue regeneration and repair.⁷⁹ Owing to its excellent biocompatibility, biodegradability, and CD44 receptor-mediated active targeting capability, HA exhibits remarkable advantages in novel drug delivery systems for cSCC.^80,81

Piao et al developed an HA-based transdermal delivery system for the co-delivery of cationic solid lipid nanoparticles (cSLNs) and siRNA targeting oncogenes. This system exploits the bioadhesive property and CD44 receptor-targeting ability of HA to significantly enhance the skin penetration efficiency and tumor cell uptake of siRNA, while effectively inhibiting tumor growth and reducing immune responses and off-target toxicity associated with systemic administration.⁸²

Choi et al designed an intelligent nanocarrier based on PEGylated hyaluronic acid (HA-PEG), in which HA serves as a targeting ligand to specifically recognize cancer cells with high CD44 receptor expression (as depicted in Figure 4). The system also integrates a stimulus-responsive release mechanism to achieve precise and controlled release of hydrophobic chemotherapeutic agents. Preclinical studies have demonstrated that this strategy effectively enhances antitumor efficacy, significantly reduces systemic toxicity, and markedly increases the therapeutic index of the drug. Such HA-based intelligent vectors provide a robust technological approach for developing highly effective and low-toxicity therapeutics for skin cancer.⁸³

Figure 4 Mechanism of CD44-targeted nanocarriers for siRNA delivery in cutaneous squamous cell carcinoma (cSCC). Abbreviations: cSCC, cutaneous squamous cell carcinoma; siRNA, small interfering RNA; CD44, cluster of differentiation 44; siRNA, small interfering RNA. Notes: (a) Targeted binding: The nanocarriers specifically recognize and bind to CD44 receptors that are highly expressed on the surface of cSCC cells, while showing no binding to normal keratinocytes with low CD44 expression, achieving tumor-selective targeting. (b) Endocytosis: The bound nanocarriers are internalized into cSCC cells via endocytosis. (c) Acidic endolysosome maturation: The internalized nanocarriers are encapsulated in endolysosomes with an acidic microenvironment (pH ~4.5–5.0), which triggers the pH-responsive structural change of the nanocarriers. (d) Endolysosomal escape: The pH-sensitive nanocarriers disrupt the endolysosomal membrane and successfully escape into the cytoplasm, avoiding degradation by lysosomal hydrolases. (e) Drug release: The nanocarriers release the loaded small interfering RNA in the cytoplasm.

Hydrogel

Hydrogels are three-dimensional network structures formed by physical or chemical crosslinking of hydrophilic polymer chains. They possess high water content, good biocompatibility, and tunable mechanical properties,⁸⁴ and have become an important platform for the local treatment of cSCC. Hydrogels can encapsulate various therapeutic agents such as chemotherapeutic drugs, nanoparticles, and biomacromolecules, forming a drug reservoir on the skin surface to achieve sustained and controlled release while providing a moist environment for wound healing. In recent years, significant progress has been made in the development of multifunctional composite hydrogels. Pandya et al developed a multifunctional hydrogel based on an ionic liquid–metal-organic framework (IL@MOF) composite for the transdermal delivery of 5-FU. This system significantly enhances drug skin permeability and antitumor efficacy by integrating the high drug-loading capacity of metal-organic frameworks (MOFs) with the sustained-release properties of hydrogels, while simultaneously reducing systemic toxicity. In addition, smart responsive hydrogels can regulate the drug release rate in response to microenvironmental changes such as temperature, pH, and enzyme activity, thereby enabling on-demand therapy.⁸⁵ Composite systems that combine the advantages of nanotechnology and hydrogels can achieve efficient drug loading, targeted delivery, and intelligent controlled release, offering new possibilities for precise local treatment of cSCC.

Advanced Therapeutic Strategies for cSCC

The clinical treatment of cSCC still faces multiple challenges, including limited efficacy, insufficient targeting, and systemic toxic side effects. In recent years, the rapid development of therapy strategies such as phototherapy synergy, nanodelivery of immune checkpoint inhibitors (ICIs), and modulation of the tumor microenvironment (TME) has provided new approaches to address these issues. These three strategies have overcome the traditional therapeutic bottlenecks in aspects such as synergistic mechanisms, delivery efficiency, and microenvironmental adaptation, offering diverse and innovative pathways for precise and efficient treatment of cSCC and demonstrating remarkable translational potential (as summarized in Table 2).⁷⁵

Table 2 Mechanisms of Action, Advantages, and Challenges of Novel Advanced Therapeutic Strategies for Cutaneous Squamous Cell Carcinoma (cSCC)

Phototherapy Synergy

Nanocarrier-Mediated Synergistic Photothermal and Photodynamic Therapy

Photodynamic therapy (PDT) and photothermal therapy (PTT) are important phototherapeutic approaches for the treatment of cSCC.⁹⁴ However, the efficacy of a single phototherapy modality remains limited. Photothermal–photodynamic nanosystems, by integrating physical and chemical therapeutic mechanisms, provide an efficient and low-toxicity combination therapy strategy for cSCC.⁸⁷ Zheng et al reported an Au25(Capt)18 gold nanocluster system that exhibits unique potential in near-infrared light-triggered photothermal–photodynamic combination therapy (PTT–PDT). Under near-infrared irradiation, the nanoclusters induce thermal apoptosis of tumor cells through efficient photothermal conversion, while simultaneously generating ROS that trigger oxidative stress and damage key organelles such as mitochondria. The photothermal effect further enhances cellular internalization and ROS sensitivity, synergistically killing tumor cells and inducing immunogenic cell death (ICD), thereby creating favorable conditions for the activation of antitumor immune responses.⁸⁶ The therapeutic efficacy of this combination therapy is significantly superior to that of PTT or PDT alone, confirming the synergistic advantages of phototherapy mediated by nanocarriers.

Responsive Nanotheranostic Systems for Precise Phototherapy

Although conventional photothermal–photodynamic nanosystems can synergistically eliminate cSCC, the nonspecific distribution of photosensitizers in normal skin often induces photosensitivity reactions. These skin responses, including erythema, edema, blistering, pigmentation, and sunburn, result in significant phototoxicity that compromises patients’ quality of life and limits the clinical application of combined phototherapy.⁸⁹ To address this issue, Zhang et al developed a nanotheranostic system responsive to both near-infrared light and the redox microenvironment. In this study, a diselenide bond was used to bridge the photosensitizer Ce6 and HA to construct an amphiphilic polymer, HSeC, which was then loaded with the photothermal agent IR780 to form HSeC/IR nanoparticles. The innovation of this system lies in maintaining the photosensitizer in a fluorescence-quenching state during circulation through the dual mechanisms of aggregation-induced quenching and fluorescence resonance energy transfer, thereby avoiding phototoxicity to normal skin. Within the tumor region, the high concentration of glutathione in the microenvironment triggers diselenide bond cleavage, while near-infrared irradiation induces IR780 degradation, achieving precise synergistic activation of PDT and PTT.⁸⁸ This system not only effectively inhibited the SCC7 cell line but also markedly alleviated the skin injuries caused by conventional photosensitizers, providing a new approach for precise phototherapy of skin cancer.

The functional modification enabled by nanotechnology serves as a key driving force for the refinement and advancement of phototherapy in cSCC treatment. A series of studies have progressively addressed the limitations of traditional phototherapy in terms of efficacy, targeting, and safety. The integration of nanotechnology with phototherapy offers an innovative strategy for personalized treatment of cSCC, and future work should further optimize drug loading and explore its synergistic potential with immunotherapy.⁹⁵

Nano-Delivery of Immune Checkpoint Inhibitors

Multidimensional Immune Microenvironment Regulation

ICIs are a class of immunotherapeutic agents that target inhibitory signaling pathways within the immune system and have been applied in the treatment of various cancers.⁹⁶ They function by blocking the inhibitory signaling pathways between T cells and tumor cells, thereby reversing tumor-induced immunosuppression and reactivating the cytotoxic activity of effector T cells.⁹⁷ However, immune-related adverse events (irAEs), limited tumor penetration, and resistance arising from the immunosuppressive microenvironment have restricted the broad clinical application of ICIs.⁹⁸ Nanodrug delivery systems (NDDSs) have demonstrated great potential in enhancing anticancer efficacy and reducing the side effects of small-molecule drugs.⁹⁹ By remodeling the immune microenvironment and coordinately regulating immune pathways,¹⁰⁰ NDDSs can effectively overcome immunotherapy resistance in cSCC. Therefore, nanoplatforms have become the preferred vectors for ICIs and their combination therapies, providing an efficient and low-toxicity therapeutic strategy for cSCC.¹⁰¹ Li et al reported a biomaterial-based delivery system utilizing CRISPR/Cas9 gene editing technology, which enables the precise delivery of editing tools into the cSCC tumor microenvironment or immune cells to achieve accurate regulation of immune checkpoint–related genes. On one hand, this system can knock out the highly expressed PD-L1 gene in tumor cells, thereby weakening their immune evasion capability; on the other hand, it can edit the PD-1 gene in T cells to enhance the cytotoxic activity of effector T cells against tumor cells, ultimately remodeling the tumor immune microenvironment.⁹⁰ By precisely editing key immune-related genes in tumor cells, this delivery system opens a new avenue for enhancing the efficacy of ICIs in skin cancer therapy, particularly through its ability to reverse the downregulation of MHC-I expression, which holds promise for addressing the core clinical challenge of ICI resistance. In addition to gene editing, targeting key signaling nodes such as cIAP1 can also enhance the efficacy of immune checkpoint inhibitors. Studies have demonstrated that the TWEAK/Fn14 signaling pathway in cSCC cells promotes proliferation by activating cIAP1, whereas the cIAP1 inhibitor MV1 can significantly block this pathway and induce tumor cell apoptosis. The combination of MV1 with an anti–PD-L1 inhibitor is expected to further improve immune response efficiency.⁹¹

pH-Responsive Nanocarrier Systems for Combined Immunotherapy and Chemotherapy Delivery

To address the challenges of low systemic co-delivery efficiency and additive toxicity of ICIs and chemotherapeutic agents, researchers developed a pH-responsive Pickering nanoemulsion (D/HY@PNE) drug delivery system co-loading the chemotherapeutic drug doxorubicin (DOX) and the immune checkpoint inhibitor HY19991 (HY). This system preferentially releases HY to modulate the tumor immune microenvironment, followed by the release of DOX into tumor cells to exert chemotherapeutic effects. This strategy not only enhances the tumor penetration of DOX but also significantly strengthens antitumor immunity through the synergistic effects of ICD induction and HY-mediated immune checkpoint blockade. Animal experiments confirmed that this system effectively improves combination therapy efficacy and, owing to its pH-responsive characteristics, reduces toxic side effects on normal skin tissue, providing a new approach for precise and low-toxicity combination immunochemotherapy for skin cancer.¹⁰²

The immune checkpoint inhibitor nanodelivery system demonstrates significant advantages in enhancing delivery efficiency, improving efficacy, and ensuring safety through precise design, providing a new technological approach for the immunotherapy of cSCC.

Strategies for Modulating the TME

Neoadjuvant Immunotherapy Reverses the Immunosuppressive Microenvironment

TME of cSCC is a complex ecosystem characterized by immunosuppression and structural abnormalities. It is primarily composed of heterogeneous tumor cells, immunosuppressive immune cells such as regulatory T cells and myeloid-derived suppressor cells, stromal cells, the extracellular matrix, and various soluble signaling molecules.¹⁰³ This immunosuppressive nature profoundly impairs the efficacy of anticancer drugs and constitutes a major obstacle to immunotherapy.¹⁰⁴ Gross et al demonstrated through a clinical research study of neoadjuvant cemiplimab (an anti–PD-1 antibody) that preoperative administration of a PD-1 inhibitor can block the interaction between PD-1 on the surface of T cells and PD-L1 expressed by tumor cells, thereby relieving tumor cell–mediated suppression of effector T cells. This process helps reverse the immunosuppressive state of the TME, promotes the infiltration and activation of cytotoxic T cells within the tumor site, and creates favorable conditions for subsequent surgery. Neoadjuvant cemiplimab induced significant pathological remission and sustained survival benefits before surgery.⁹² This strategy of advancing systemic immunotherapy provides a new paradigm for perioperative treatment of locally advanced cSCC.

Vascular Normalization for cSCC TME Remodeling

The key to overcoming the therapeutic bottleneck of ICIs lies in a thorough understanding and precise modulation of the TME in cSCC. Studies have shown that the TME of cSCC possesses a complex immunosuppressive network, and abnormal vascular structures hinder effective drug delivery. Dong et al conducted an in-depth analysis of the cSCC TME and revealed its intricate immunosuppressive network,¹⁰⁵ in which aberrant vascular architecture represents a major barrier to efficient drug transport.¹⁰⁶ Consequently, in the field of skin cancer, strategies for anti-angiogenic therapy have shifted from the initial inhibition of angiogenesis to the normalization of blood vessels. Although traditional VEGF inhibitors have been applied in cSCC and melanoma, they tend to exacerbate tumor hypoxia. In recent years, the “vascular normalization” theory proposed by Jain and others has provided new insights into anti-angiogenic therapy. This approach emphasizes the precise regulation of VEGF signaling to improve vascular structure and function, enhance tumor perfusion, alleviate hypoxia, thereby increasing sensitivity to chemoradiation and remodeling the immune microenvironment. Clinical practice has shown that combining the vascular normalization strategy with PD-1/PD-L1 inhibitors can synergistically promote CD8⁺ T cell infiltration and improve the objective response rate, demonstrating significant therapeutic value in cSCC.⁹³

Neoadjuvant immunotherapy and blood vessel normalization strategies remodel the tumor microenvironment of cSCC through different pathways. Both demonstrate potential synergistic effects with existing treatment modalities, providing new directions for the precise treatment of cSCC.

Current Status, Challenges, and Future Directions of Clinical Translation

As outlined in Table 3, although novel drug delivery systems based on nanocarriers and microneedles have demonstrated substantial therapeutic potential for cSCC in preclinical studies, their translation from the laboratory to clinical application still faces multiple challenges. A systematic review of the current translational progress, an in-depth analysis of the key obstacles, and the formulation of a clear developmental roadmap are of great significance for advancing this field.

Table 3 Translational Landscape, Challenges, and Future Directions of Novel Drug Delivery Systems for Cutaneous Squamous Cell Carcinoma (cSCC)

Current Status of Clinical Translation

In recent years, novel therapeutic strategies for cSCC, particularly those based on materials and delivery methods for localized administration, have achieved remarkable progress. In the field of nanocarriers, certain liposomes and polymeric nanoparticles, owing to the relative maturity of their material systems, have already undergone clinical translation in other disease areas,¹⁰⁷ providing valuable insights for the development of nanomedicines targeting cSCC. Among local delivery technologies, MN arrays, with their advantages of being painless and minimally invasive, have led to the commercialization or clinical research of multiple products in vaccine delivery and categories of skin disease, thereby paving the way for their application in cSCC therapy. In addition, researchers have developed artificial intelligence–driven hydrogel MN patches for the delivery of flexible PEGylated liposomes encapsulating 5-fluorouracil. In vitro experiments demonstrated a high skin penetration rate as well as significant inhibitory and pro-apoptotic effects on cancer cell growth.¹⁰⁸ In addition, dissolvable microneedles loaded with polydopamine nanoparticles were found to induce polarization of tumor-associated macrophages and maturation of dendritic cells, showing promise for tumor immunotherapy.⁶⁵ Meanwhile, composite hydrogels remain at the preclinical research stage; although these material systems are complex and highly functional, large-scale biosafety and long-term toxicity evaluations are still required before clinical application.¹⁰⁹ Furthermore, photothermal–photodynamic nanosystems and immune checkpoint inhibitor nano-delivery systems have also exhibited marked tumor-suppressive effects in animal models. Their potential for clinical translation has been widely recognized, and some candidate therapeutics are currently in the critical transition phase from preclinical to clinical trials. Although the aforementioned technologies have shown promising preclinical results, the clinical translation of more innovative multifunctional synergistic systems remains in its infancy and urgently requires validation through standardized clinical research.

Core Challenges

The translation of novel drug delivery technologies for cSCC from laboratory research to clinical application faces numerous core challenges, fundamentally stemming from the gap between ideal concepts and practical realities. First, the biosafety and regulatory compliance of new materials are primary considerations, encompassing issues such as long-term toxicity, biodegradability, in vivo metabolic pathways, and immunogenicity. The approval process for such complex products is therefore highly rigorous.¹¹⁰ Second, large-scale manufacturing and quality control constitute key bottlenecks in achieving clinical translation. A substantial gap exists between gram-scale synthesis in the laboratory and kilogram-scale production in industrial settings,¹¹⁷ where batch manufacturing often struggles to maintain uniform particle size of carrier materials and consistent drug encapsulation efficiency. Furthermore, novel drug delivery technologies must demonstrate clear clinical advantages over standard therapies, such as higher complete response rates, lower recurrence rates, or shorter healing times.¹¹¹ However, these systems often possess dual attributes of both pharmaceuticals and medical devices, while the existing regulatory frameworks lack specific standards. For instance, unified guidelines are still absent for evaluating the mechanical strength of microneedle products or quantifying drug delivery efficiency, resulting in complex approval procedures. Finally, the limited predictive power of disease models represents another major challenge.¹¹² Simple two-dimensional cell lines and subcutaneous xenograft tumor models fail to replicate the authentic microenvironment of human cSCC, leading to situations where therapies effective in animal models ultimately prove unsuccessful in clinical trials.¹¹³

To overcome the aforementioned challenges, future development should focus on several key directions. To address issues related to material biosafety and regulatory compliance, integrated testing platforms based on biomimetic microfluidic chips can be developed to enable high-throughput screening of material toxicity, degradation rate, and immunogenicity. In addition, more reliable models—such as 3D models and organoids—should be established to systematically evaluate their long-term toxicity, in vivo fate, and immunogenicity.¹¹⁴ To bridge the gap between laboratory research and industrial-scale production,¹¹⁵ a deeper integration of engineering and materials science is required. Advanced manufacturing approaches, including microfluidic technology and continuous-flow production processes, should be adopted to enhance the reproducibility and scalability of nanocarrier synthesis. Meanwhile, quality control standards suitable for complex delivery systems should be established, and real-time process analytical technologies based on artificial intelligence should be explored to ensure product quality consistency. In response to regulatory challenges, it is imperative to advance regulatory science research to establish appropriate evaluation frameworks for combination products that integrate the characteristics of both drugs and medical devices. The successful development of nanomedicines must adopt regulatory-compliant translational strategies from the outset,¹⁰⁶ while strengthening close collaboration among academia, industry, and regulatory authorities to jointly formulate rational technical review requirements. For example, standardized testing protocols should be developed for assessing the mechanical strength of microneedle products, evaluating skin penetration, and quantifying delivery efficiency. To bridge the gap between preclinical and clinical research, more predictive disease models should be developed, such as humanized mouse models, patient-derived xenograft models, and ex vivo culture models based on patient tumor tissues, so as to better preserve the complexity of the tumor microenvironment. In addition, skin cancer models constructed using 3D bioprinting technology offer new possibilities for simulating the tumor immune microenvironment and evaluating immunomodulatory delivery systems.¹¹⁶

Conclusion

This article reviews the latest research progress in drug delivery strategies for cSCC. With the emergence of novel drug delivery systems, the therapeutic landscape for cSCC is undergoing profound changes. Novel delivery systems such as nanocarriers, cell-penetrating peptide modification technology, DNA nanocomposites, microneedle arrays, and hyaluronic acid-based carriers provide promising solutions to overcome the limitations of conventional therapies in terms of targeting, permeability, and adverse effects. These delivery systems can precisely transport drugs to tumor sites and further enhance antitumor efficacy through synergistic combination with phototherapy, immune checkpoint blockade, and tumor microenvironment modulation.

Although these nanotechnology-based delivery strategies have demonstrated great potential in preclinical studies for cSCC, their clinical translation remains challenged by tumor heterogeneity, insufficient tissue penetration, challenges in large-scale manufacturing, and unclear regulatory pathways. Future research should strike a balance between innovation and practicality, focusing on the design of simplified and reliable delivery systems to address key therapeutic bottlenecks in cSCC, while integrating clinical needs and industrialization requirements in material development and carrier design.

In summary, research on novel drug delivery systems for cSCC is at a critical stage transitioning from fundamental exploration to clinical translation. Continued innovation in materials science, in-depth understanding of cSCC biological characteristics, and multidisciplinary cross-collaboration are expected to drive the development and clinical application of these strategies, ultimately providing patients with cSCC more efficient, precise, and safer treatment options, thereby improving clinical outcomes.