Smart and stimuli-responsive hydrogels for controlled exosome delivery in bone tissue engineering: from passive...

Bone regeneration follows a tightly coordinated biological sequence in which inflammatory resolution, vascular formation, and matrix mineralization occur within distinct temporal windows. However, most current exosome delivery strategies primarily extend retention rather than synchronize therapeutic signaling with these dynamic healing stages. This mismatch between release kinetics and biological demand may limit the regenerative potential of extracellular vesicle therapies. This review proposes a biology-driven framework that reinterprets stimuli-responsive hydrogel systems according to their capacity to coordinate stage-specific exosome delivery throughout bone healing. Recent literature on hydrogel-based exosome delivery systems was critically analyzed and interpreted according to their ability to regulate therapeutic timing rather than stimulus type, encompassing endogenous-responsive, externally triggered, and hybrid platforms. Particular emphasis was placed on release kinetics, osteoimmunomodulation, angiogenic coupling, translational feasibility, and emerging adaptive delivery concepts. Current preclinical evidence suggests that stimuli-responsive hydrogels capable of synchronizing exosome release with successive stages of bone healing may improve inflammatory regulation, vascularization, and osteogenesis compared with passive delivery systems. However, these biological effects remain dependent on hydrogel formulation, exosome source, and experimental model. Multi-responsive and adaptive platforms appear particularly promising for achieving sequential therapeutic signaling, although most remain at the proof-of-concept or preclinical stage. Rather than functioning solely as sustained-release carriers, future exosome delivery systems are likely to evolve toward adaptive therapeutic platforms capable of integrating microenvironment sensing with programmable release behavior. The biology-driven framework proposed in this review provides a complementary perspective for the rational design of next-generation regenerative biomaterials while highlighting the key experimental and translational challenges that must be addressed before clinical implementation.