Extracellular vesicle encapsulated mesoporous molecularly imprinted silica for peptide drug delivery.

Peptide therapeutics have demonstrated remarkable efficacy in the treatment of metabolic disorders (GLP-1 analogs), cancers (targeted tumor receptor inhibition), and infectious diseases (antimicrobial/viral entry blockade mechanisms), yet their clinical application remains constrained by rapid in vivo degradation and limited transmembrane permeability due to macromolecular polarity. To address these challenges, we developed a biomimetic nano-delivery system (EV@DhHP-6-MIP) synergizing milk-derived extracellular vesicles (EVs) with molecularly imprinted mesoporous silica through ultrasound-assisted membrane fusion technology. The molecularly imprinted mesoporous silica, featuring surface-imprinted binding sites on its ordered 3.1 ± 0.3 nm channels, achieved high-efficiency loading of the antioxidative peptide DhHP-6. The EVs enhanced targeted delivery via CD63/TSG101 transmembrane protein-mediated receptor-dependent endocytosis, while their natural phospholipid bilayer structure minimized immunogenicity compared to synthetic carriers. Leveraging milk as a renewable resource, this system ensured scalable production feasibility. In vitro evaluation using human embryonic kidney 293 T cells-selected for their well-characterized endocytic mechanisms and stable oxidative stress response-demonstrated that EV@DhHP-6-MIP reduced intracellular ROS levels by 38.5 %. For in vivo validation, Caenorhabditis elegans, which shares evolutionarily conserved oxidative stress pathways with humans, was employed. EV@DhHP-6-MIP treatment extended nematode survival time by 31.2 % under paraquat-induced oxidative stress and reduced intestinal lipofuscin accumulation by 40.47 %, without observable reproductive toxicity. This system resolves the longstanding conflict between protective encapsulation and bioavailability enhancement in peptide drug delivery through a tripartite synergistic mechanism: mesoporous silica-enabled drug stabilization, molecular imprinting-driven controlled release, and EV-mediated efficient delivery. Our work establishes a theoretical paradigm for developing intelligent nano-drug delivery systems with high efficacy and low toxicity, thereby holding significant translational value.