Peptidyl Virus‐Like Nanovesicles as Reconfigurable “Trojan Horse” for Targeted siRNA Delivery and Synergistic Inhibition of Cancer Cells

The self‐assembly of peptidyl virus‐like nanovesicles (pVLNs) composed of highly ordered peptide bilayer membranes that encapsulate the small interfering RNA (siRNA) is reported. The targeting and enzyme‐responsive sequences on the bilayer's surface allow the pVLNs to enter cancer cells with high efficiency and control the release of genetic drugs in response to the subcellular environment. By transforming its structure in response to the highly expressed enzyme matrix metalloproteinase 7 (MMP‐7) in cancer cells, it helps the siRNA escape from the lysosomes, resulting in a final silencing efficiency of 92%. Moreover, the pVLNs can serve as reconfigurable “Trojan horse” by transforming into membranes triggered by the MMP‐7 and disrupting the cytoplasmic structure, thereby achieving synergistic anticancer effects and 96% cancer cell mortality with little damage to normal cells. The pVLNs benefit from their biocompatibility, targeting, and enzyme responsiveness, making them a promising platform for gene therapy and anticancer therapy. Peptidyl virus‐like nanovesicles (pVLNs) composed of bilayer membranes are assembled by the peptides and siRNA. The targeting and enzyme‐responsive sequences on the bilayer's surface allow the pVLNs to enter cancer cells with high efficiency and control the release of genetic drugs in response to the subcellular environment. The resulting gene silencing efficiency is 92% and cancer cell mortality is 96%.