Nanocarrier mediated microRNA delivery for oral squamous cell carcinoma a scoping review of delivery architecture preclinical efficacy and translational barriers.

BACKGROUND

For thirty years, the five-year survival rate for oral squamous cell carcinoma (OSCC) has remained below 60%. One major limitation is the absence of delivery systems that can take advantage of the molecular weaknesses unique to OSCC. MicroRNAs (miRNAs) control tumor-suppressive and carcinogenic pathways post-transcriptionally, but their therapeutic application is hindered by endosomal sequestration, low cellular uptake and quick nuclease-mediated destruction. These obstacles are addressed by nanocarrier platforms, while translational evidence unique to OSCC is dispersed.

METHODS

A scoping review was conducted following PRISMA-ScR guidance. PubMed/MEDLINE, Scopus, Web of Science and Google Scholar were searched from January 2014 to March 2025 using Boolean search strings combining miRNA delivery, nanocarrier platform and OSCC terminology. Original research articles and early-phase clinical trials reporting quantitative preclinical or clinical outcomes were eligible. Two independent reviewers screened records; data were extracted on nanocarrier type, miRNA cargo, biological targets, efficacy metrics, toxicity and regulatory status.

RESULTS

Sixty-one studies met eligibility criteria. Liposomes (n = 18), polymeric nanoparticles (n = 17), lipid nanoparticles (n = 10), dendrimers (n = 9) and inorganic carriers (n = 7) were the dominant platforms. Tumor-suppressive miR-34a, miR-145, miR-200c and miR-199a-3p demonstrated the most consistent preclinical efficacy, with tumor volume reductions of 38-65% in OSCC xenograft models. Stimulus-responsive systems improved intratumoral miRNA availability by limiting premature cargo release. Immunogenicity, hepatic off-target accumulation and manufacturing scale-up were the dominant translation barriers. The MRX34 phase I trial, the only completed human study, was terminated due to cytokine release syndrome.

CONCLUSION

Nanocarrier-mediated miRNA delivery shows encouraging preclinical evidence in OSCC, largely from immunodeficient xenograft systems, but mechanistic heterogeneity, immunogenicity and the absence of standardized preclinical models impede clinical translation. Future development may benefit from prioritizing ionizable lipid formulations with defined immunocompatibility profiles, biomarker-stratified patient selection and orthotopic immune-competent OSCC models. Clinical trial number Not applicable.