Next-generation miRNA therapeutics: from computational design to translational engineering.

MicroRNAs (miRNAs ) are emerging as powerful therapeutic agents for metastatic cancers due to their ability to modulate multiple oncogenic pathways simultaneously. However, their clinical translation remains hindered by challenges such as poor stability, limited tumor specificity, off-target effects, and inadequate delivery systems. This review presents a comprehensive analysis of recent advances in the use of cationic polymer-based nanocomplexes for the multiplexed delivery of tumor-suppressive miRNAs. These nanoplatforms offer structural versatility, tunable surface chemistry, and responsive release mechanisms, enabling co-delivery of multiple miRNAs to synergistically regulate key steps in the metastatic cascade, including epithelial-mesenchymal transition (EMT), invasion, immune evasion, and colonization. We further dissect the structural design principles of polymeric carriers, targeting strategies tailored for the tumor microenvironment, and emerging methods for achieving spatiotemporal control over miRNA release. The concept of "intelligent, multi-targeted, and personalized" miRNA nanomedicine is proposed to address tumor heterogeneity and therapeutic resistance. Importantly, we highlight the major translational barriers, including immunogenicity of cationic polymers, difficulties in large-scale and reproducible synthesis, and the absence of regulatory frameworks specific to combinatorial miRNA nanotherapeutics. Integrating insights from polymer science, cancer biology, and clinical pharmacology, this review aims to guide the rational design of next-generation miRNA delivery systems and accelerate their transition from bench to bedside in the era of precision oncology.