Engineering mRNA Delivery Systems for Cutaneous Wound Healing: Formulation Strategies and Translational Challenges

Chronic non-healing wounds create major clinical challenges for medical professionals because these wounds sustain ongoing inflammation while their blood vessel development remains disrupted and their tissue healing processes take longer to complete. The traditional methods, which involve using recombinant proteins and cell-based therapies, face limitations: these products degrade quickly, they lack effective control over distribution and timing, their production processes are highly complex, and they require multiple treatments, which creates a pressing demand for therapies that provide precise control over temporary protein production at specific locations. mRNA therapeutics address this gap by enabling transient, non-integrative, and tunable protein expression directly within target cells, offering precise spatiotemporal control over therapeutic activity. This review examines engineering strategies that enhance mRNA-based regenerative therapies for wound healing. The main transcript optimisation methods, including nucleoside modification, untranslated region (UTR) design, cap structure refinement, and poly(A) tail engineering, enhance mRNA stability, translation efficiency, and immune modulation. This review further examines advanced delivery systems, including lipid nanoparticles, polymeric carriers, hydrogels, and extracellular vesicle-based platforms, that protect mRNA, enhance cellular uptake, facilitate endosomal escape, and support tissue retention in RNase-rich wound environments. The review also highlights considerations related to PK (pharmacokinetics), biodistribution, repeat dosing, scalability, and regulatory challenges. This review critically evaluates engineering strategies from transcript optimisation to advanced delivery systems that enable controlled, local protein expression. We identify key formulation challenges in the protease-and RNase-rich wound microenvironment and propose a framework to bridge preclinical promise with clinical reality for chronic wound management.