Recent advances in hybrid membrane vesicles as a programmable biomimetic drug delivery

Biomimetic nanomedicine utilizing cell membrane cloaking has emerged as a promising approach to enhance nanocarrier performance by integrating the physicochemical benefits of synthetic nanoparticles with the biological functionalities of source cells. Nonetheless, single-source membrane systems are inherently limited by their restricted functionality, which constrains their capacity to address the complex pathological barriers present in various diseases. To address these limitations, hybrid membrane vesicles (HMVs) have been developed. These vesicles are formed by the fusion of two or more distinct membrane types and are engineered biomimetic platforms designed to integrate selected membrane-derived functions within a unified nanoscale architecture. By integrating membrane-derived functions, HMVs provide a modular framework for combining biological recognition with engineered cargo delivery. However, whether these functions are complementary or genuinely synergistic depends on the membrane architecture and the controls used for validation. Unlike previous reviews that mainly focus on single-source membrane-coated nanoparticles, extracellular vesicles (EVs), or general biomimetic nanomedicine, this Review defines HMVs as a distinct programmable biointerface platform and provides a membrane-combination-centered framework for understanding their design principles, functional complementarity, and translational challenges. Therefore, in this review, we systematically summarize the engineering strategies for constructing HMVs and propose a classification framework based on membrane origin. We focus on cancer-oriented HMVs and discuss how different membrane combinations can be rationally engineered to improve multimodal antitumor therapy. Although HMVs also show potential in other diseases, these non-cancer applications are discussed only as supportive examples to illustrate generalizable design principles. We further analyze how particular membrane combinations create functional complementarity to enhance efficacy through coordinated targeting and immune activation. Finally, we examine the significant challenges impeding clinical translation. Overall, current evidence supports HMVs as flexible preclinical platforms for integrating membrane-derived recognition with engineered drug delivery functions. However, their clinical translation will require more rigorous validation of membrane architecture, GMP-compatible manufacturing, bacterial membrane-associated immunogenicity, regulatory classification, pharmacokinetics, metabolic fate, and long-term safety.