Biomaterial Platforms for Spatiotemporal Control of mRNA Delivery in Tissue Engineering and Regenerative Medicine: Design Rules, Therapeutic Applications, and Translational Roadmap

ABSTRACT Messenger RNA (mRNA) enables transient, non‐integrating, and programmable protein expression, yet its regenerative potential is constrained by extracellular instability, inefficient cytosolic delivery, rapid tissue clearance, innate immune activation, and poor alignment between expression kinetics and healing programs. Biomaterial platforms address these barriers by integrating molecular protection and intracellular delivery with local retention, controlled release, biophysical support, and microenvironmental regulation. This Review critically examines nanoscale carriers, macroscale depots and scaffolds, and hierarchical nano‐in‐matrix and stimulus‐responsive systems for spatiotemporally controlled mRNA delivery. We propose a cargo–target–timing framework linking mRNA chemistry and material properties to delivery, expression, immune responses, and tissue repair. Evidence across musculoskeletal, cardiovascular, neural, cutaneous, and visceral tissues is assessed to identify candidate expression profiles, their biological rationale, and the comparative studies needed to define therapeutic windows. Critical quality attributes, longitudinal monitoring, cross‐study comparability, manufacturing, storage, dosing, safety, clinically relevant models, and regulatory positioning are evaluated. Finally, a stage‐gated translational roadmap and artificial intelligence (AI)‐enabled, adaptive, and personalized design strategies are presented. By integrating structure–property relationships with tissue‐specific therapeutic windows and product‐development requirements, this Review establishes actionable principles for advancing mRNA‐biomaterial systems toward regenerative products.