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RNA-based therapeutics have emerged as promising strategies for treating infectious diseases, cancer, and genetic disorders owing to their ability to regulate gene expression with high specificity. However, their clinical translation remains limited by poor physiological stability, rapid nuclease degradation, inefficient cellular uptake, endosomal entrapment, and unintended immune activation. Nanomaterial-based delivery systems have therefore become essential for protecting RNA cargo, improving intracellular transport, and enabling controlled cytosolic release. This review critically examines recent advances in nanomaterial-enabled RNA delivery platforms, including lipid nanoparticles, polymeric carriers, inorganic nanomaterials, and hybrid biomimetic systems, with emphasis on how nanocarrier physicochemical properties influence RNA loading, biodistribution, cellular internalisation, and endosomal escape. Unlike conventional reviews that separately discuss RNA modalities or delivery systems, this review integrates nanocarrier design, biological barriers, intracellular trafficking, and translational feasibility within a unified design-to-clinic framework, while comparatively analysing why lipid nanoparticles have achieved clinical success whereas many alternative platforms remain translationally limited. Major biological barriers and engineering strategies, including surface functionalization, ligand-mediated targeting, and stimuli-responsive architectures, are systematically correlated with therapeutic outcomes. The review further highlights key translational design principles underlying clinically successful RNA nanotherapeutics, including balancing systemic stability, efficient endosomal escape, biocompatibility, targeted biodistribution, and scalable manufacturing. Representative clinically approved and late-stage systems are discussed alongside current translational limitations, safety concerns, and regulatory challenges. Finally, emerging directions involving artificial intelligence-guided nanocarrier engineering, biomimetic delivery systems, and multifunctional co-delivery platforms are outlined to support the future development of clinically viable RNA therapeutics.
Pandey et al. (Tue,) studied this question.