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Extracellular vesicles (EVs) hold great promise as natural carriers, yet conventional loading methods, most notably electroporation, suffer from low encapsulation efficiency, structural damage, and poorly characterized aggregation artifacts. Using single-particle nano-flow cytometry, we deconvoluted these electroporation-induced artifacts and revealed that true loading efficiency is only \u223c24%. To overcome these limitations, we engineered CD47-functionalized EV\u2013liposome hybrid vesicles via membrane fusion of CD47-overexpressing EVs with siRNA-loaded liposomes. The hybrid design integrates the high payload capacity of synthetic liposomes with the intrinsic biocompatibility and immune-evasive functionality of CD47-engineered EVs. In a Transwell coculture model simulating the competitive uptake environment of the tumor microenvironment, the hybrid vesicles evaded macrophage clearance and delivered anti-PD-L1 siRNA to tumor cells, resulting in \u223c60% PD-L1 gene silencing, three times that of electroporation (\u223c20%). By providing a rationally designed hybrid nanocarrier with validated immune-evasive and RNAi performance, this work offers a significant advancement for EV-based RNA interference (RNAi) therapeutics.<\/jats:p>","DOI":"10.1021\/acsami.6c16943","type":"journal-article","created":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T15:02:20Z","timestamp":1791990140000},"page":"57300-57311","source":"Crossref","is-referenced-by-count":0,"title":["Single-Particle Deconvolution of Electroporation Artifacts Guides the Rational Engineering of CD47-EV\u2013Liposome Hybrids for siRNA Delivery"],"prefix":"10.1021","volume":"18","author":[{"given":"Xiaozhen","family":"Zhan","sequence":"first","affiliation":[{"name":"Xiamen University , , , ,","place":["Xiamen, Fujian, China, 361005"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yurou","family":"Li","sequence":"additional","affiliation":[{"name":"Xiamen University , , , ,","place":["Xiamen, Fujian, China, 361005"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Chen","sequence":"additional","affiliation":[{"name":"Xiamen University , , , ,","place":["Xiamen, Fujian, China, 361005"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niangui","family":"Cai","sequence":"additional","affiliation":[{"name":"Xiamen University , , , ,","place":["Xiamen, Fujian, China, 361005"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingyuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Xiamen University , , , ,","place":["Xiamen, Fujian, China, 361005"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunyun","family":"Hu","sequence":"additional","affiliation":[{"name":"Xiamen University , , , ,","place":["Xiamen, Fujian, China, 361005"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7482-6863","authenticated-orcid":true,"given":"Xiaomei","family":"Yan","sequence":"additional","affiliation":[{"name":"Xiamen University , , , ,","place":["Xiamen, Fujian, China, 361005"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,10,14]]},"reference":[{"issue":"7","key":"2026102802073838100_cit1","doi-asserted-by":"publisher","first-page":"441","DOI":"10.1038\/d41573-020-00078-0","article-title":"RNA therapeutics on the rise","volume":"19","author":"Wang","year":"2020","journal-title":"Nat. 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