Nanotechnology-enabled miRNA delivery systems next-generation molecular strategies in cancer therapy.

MicroRNAs (miRNAs) regulate cancer-relevant pathways but are limited clinically by instability, immune activation, and inefficient uptake. Nanotechnology offers platforms that protect and target miRNAs to tumors while enabling controlled release and intracellular delivery. This review focuses on lipid-based systems (including functionalized lipid nanoparticles (LNPs)), polymeric nanoparticles, dendrimers, and responsive hydrogels/nanogels, emphasizing comparative performance and translational readiness. We outline key barriers-enzymatic degradation, rapid clearance, endosomal trapping, off-target effects, and manufacturability-and highlight practical solutions such as poly (ethylene glycol) (PEG) coating (PEGylation)/stealthing to prolong circulation, ligand-directed targeting to enhance specificity, ionizable/fusogenic chemistries for endosomal escape, and standardized evaluation to improve reproducibility. Recent preclinical studies illustrate meaningful antitumor activity and improved tolerability for several platforms, while clinical experiences underscore the need for rigorous safety assessment and scalable production. We conclude with a concise roadmap that prioritizes platform selection for near-term translation and integration with tumor-specific miRNA signatures to advance personalized therapy. Our translation-first synthesis links barriers to design solutions (pKa-tuned LNPs; exosome-mimetic/hybrid vesicles) and highlights AI/ML-guided formulation; lessons from MRX34/TargomiRs inform safety, scalability, and CMC-together yielding a practical 24-36-month roadmap toward clinical readiness, with functionalized LNPs best positioned for near-term translation.