Non-viral and non-lipid nanoparticles for RNA therapeutics: Design, applications, and preclinical studies.
RNA therapeutics have emerged as versatile platforms for gene modulation and protein expression in vaccination, oncology, genetic disorders, and inflammatory diseases. However, their broader clinical application remains limited by inefficient delivery, insufficient tissue specificity, inadequate intracellular bioavailability, and long-term safety concerns. This review examines non-viral and non-lipid RNA nanocarriers from mechanistic and translational perspectives. We outline the cargo-specific delivery requirements of various RNA modalities and analyze polymeric nanoparticles, inorganic nanomaterials, peptide- and protein-based carriers, and virus-like particles as distinct strategies to overcome extracellular, tissue-level, cellular, and intracellular barriers. Cross-platform trade-offs are evaluated based on RNA association and release, cargo compatibility, administration route, biodegradability, immune interactions, and manufacturability. We further discuss how carrier architecture influences biodistribution, intracellular RNA activity, and therapeutic efficacy across major disease areas. Clinically validated lipid nanoparticle (LNP) formulations serve as translational benchmarks, while non-lipid systems are evaluated based on productive delivery, release efficiency, repeat-dose compatibility, long-term material fate, scalability, and regulatory feasibility. By integrating cargo requirements, barrier resolution, intracellular trafficking, and translational benchmarking, this review highlights non-viral and non-lipid nanocarriers as complementary platforms for context-specific RNA therapy.