Advanced extracellular vesicle therapeutics: From molecular engineering to intelligent devices

Extracellular vesicles (EVs) are increasingly recognized as programmable biologics with broad therapeutic potential across diverse diseases. However, their clinical translation is hindered by limited therapeutic efficiency due to poor target engagement and rapid clearance by the mononuclear phagocyte system, together with insufficient control over in vivo exposure profiles and release kinetics required for sustained, site-specific activity. This review summarizes recent advances aimed at overcoming these limitations, focusing on two complementary approaches. First, we discuss molecular engineering strategies of EVs to improve the intrinsic therapeutic potential. These include donor-cell engineering to molecularly regulate vesicle biogenesis and cargo sorting, and molecular-level chemical tailoring of native vesicles that stabilize membranes, enable selective cargo loading, or preserve vesicle identity. Second, we examine intelligent device-based technologies that improve EVs behavior in vivo by programming protection, retention, and controlled release. Functional hydrogels, bioelectronic interfaces, and microstructured carriers offer protection from degradation, couple release to disease-relevant cues, and enhance their accumulation in target tissues. We conclude by highlighting key mechanistic insights, persistent translational bottlenecks, and emerging opportunities for developing programmable and pathology-adaptive EV therapeutics. Together, these advances help establish a framework for transforming EVs from promising experimental biologics into precise, durable, and clinically scalable medicines. STATEMENT OF SIGNIFICANCE: Extracellular vesicles (EVs) are increasingly recognized as therapeutically relevant biologics, but their clinical translation remains limited by poor target-site accumulation, rapid systemic clearance, and insufficient control over in vivo exposure and release kinetics. This review addresses these barriers from a biomaterials perspective by integrating two complementary strategies: engineering the vesicle itself and engineering the delivery environment. Specifically, it discusses how donor-cell programming and molecular tailoring can improve EV composition, stability, and biological activity, while biomaterial- and device-based platforms such as hydrogels, bioelectronic interfaces, and microstructured carriers can enhance protection, local retention, and controlled release in vivo. By bridging EV biology with biomaterials-enabled delivery strategies, this review provides a unified framework for the development of programmable and pathology-adaptive EV therapeutics. The concepts summarized here are relevant to the design of next-generation biomaterial-assisted biologics with improved precision, durability, and translational potential.