RNA Nanotechnology for Reversal of Melanoma Immunotherapy Resistance

Abstract

Purpose: Cancer immunotherapy works by targeting immune and cancer cell checkpoints to induce long-term anti-tumor responses, showing effectiveness in inhibiting tumor growth and preventing recurrence. However, clinical trials have also reported side effects, as well as resistance in some patients with melanoma, prompting the integration of nanotechnology with immunotherapy to improve outcomes. RNA nanotechnology has emerged as a transformative approach in cancer immunotherapy, particularly in the context of treating melanoma. The review also highlights the challenges and future directions of RNA nanotechnology-mediated cancer immunotherapy in melanoma, underscoring its potential to transform treatment strategies. Methods: A narrative review of the recent literature was conducted, focusing on RNA nanotechnology applications in melanoma immunotherapy. Studies investigating RNA-based nanoparticles, RNA delivery systems, immune checkpoint modulation, cytokine regulation, tumor antigen vaccines, and immune-cell-targeted therapeutic strategies were evaluated and summerized. Results: RNA nanotherapeutics have demonstrated the ability to modulate immune checkpoints, reprogram tumor-associated macrophages, enhance antigen presentation, and restore T-cell activity in melanoma models. Lipid nanoparticles, polymeric nanocarriers, and bio-inspired delivery systems have shown improved RNA stability, tumor targeting, and endosomal escape. Emerging clinical evidence from RNA vaccines indicates encouraging immunogenicity and therapeutic potential in advanced melanoma. However, several barriers remain, including tumor heterogeneity, limited penetration into immune-desert metastases, nanoparticle-associated toxicity, manufacturing complexity, and variability of the enhanced permeability and retention effect in human tumors. Conclusion: RNA nanotechnology represents a promising and rapidly evolving platform for melanoma immunotherapy. By enabling precise modulation of immune responses and improving targeted therapeutic delivery, RNA-based nanostructures may overcome several limitations of current immunotherapeutic approaches. Further preclinical and clinical investigations are required to optimize safety, delivery systems, and therapeutic efficacy before widespread clinical implementation can be achieved.

Keywords: Melanoma, Immunotherapy, RNA, RNAi, Nanoparticles