Bio-intelligent delivery systems for regenerative medicine: From living biomaterials to clinical translation

Bio-intelligent delivery systems are redefining the boundaries of regenerative medicine, moving the field beyond passive scaffolds toward platforms that actively sense, respond to, and participate in tissue repair. This review examines how living cells, cell-derived extracellular vesicles, stimuli-responsive matrices, and closed-loop wearable devices can be integrated into a coherent therapeutic design framework and what stands between these systems and routine clinical use. We begin by analyzing the paracrine biology of mesenchymal stem cells, focusing on how immunomodulatory mediators and extracellular vesicles orchestrate repair, and why donor variability and context-dependent licensing continue to constrain clinical predictability. Building on this, we compare five classes of living delivery platforms - cell-laden hydrogels, secretome- and vesicle-loaded matrices, microcapsule systems, and microneedle constructs, evaluating their capacity to sustain cell viability, regulate release kinetics, and improve local retention over bolus injection. Precision targeting strategies employing surface functionalization and peptide-mediated homing are assessed across cardiac, hepatic, and pulmonary contexts. Smart biomaterials responsive to pH, temperature, and reactive oxygen species are then evaluated for their ability to synchronize therapeutic delivery with the dynamic phases of tissue repair. Wearable biosensing platforms and three-dimensional bioprinted constructs are discussed as next-generation tools for closed-loop, patient-adaptive therapy. Throughout, we identified scale-up inconsistency, immunogenicity, regulatory fragmentation, and the absence of validated potency assays as recurring translational barriers. We conclude that convergence of GMP-compatible biomanufacturing, harmonized regulation, and artificial intelligence-assisted design is necessary to advance these platforms from preclinical promise to reproducible, patient-specific clinical practice.