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Here, Lactobacillus helveticus-derived exosomes (LHexo) were dual-functionalized with mannose and cRGD (McRLHexo), yielding improved membrane lipid ordering, denser PEG brush layer, and distinct \u201ccloud-like\u201d surface nanostructure. McRLHexo exhibited enhanced stability under UV (transmittance reduction &amp;gt; 98%), thermal, and digestive conditions (drug retention &amp;gt;86%), and increased pterostilbene (PTS) loading. Functionally, McRLHexo@PTS achieved efficient epithelial translocation via cRGD-integrin pathways and macrophage targeting via Man\/cRGD dual-recognition. In DSS-induced colitis mice, McRLHexo showed optimal targeting accumulation and uptake in the colon. Importantly, McRLHexo@PTS markedly alleviated colitis, restoring body weight, colon length, and epithelial integrity while reducing inflammatory cytokines and oxidative stress and enhancing antioxidant defenses. This study establishes a dual-targeted probiotic exosome platform for oral therapy and provides insights into ligand-membrane engineering for precision intestinal delivery.<\/jats:p>","DOI":"10.1021\/acs.jafc.5c16503","type":"journal-article","created":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T17:01:34Z","timestamp":1790442094000},"page":"31080-31100","source":"Crossref","is-referenced-by-count":0,"title":["Mannose-cRGD Engineered\n                    <i>Lactobacillus helveticus<\/i>\n                    -Derived Exosomes Enhance Loaded Pterostilbene\nBioavailability: From Dual Insights of Membrane Lipid Orderliness\nand Dual-Targeting Endocytosis Modulation"],"prefix":"10.1021","volume":"74","author":[{"given":"Qiu-Ya","family":"Ji","sequence":"first","affiliation":[{"name":"Hefei University of Technology , , 193 Tunxi Road , , ,","place":["Hefei, Anhui, PR China, 230009"]},{"name":"Hefei University of Technology , , 193 Tunxi Road , , ,","place":["Hefei, Anhui, PR China, 230009"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ran","family":"Meng","sequence":"additional","affiliation":[{"name":"Hefei University of Technology , , 193 Tunxi Road , , ,","place":["Hefei, Anhui, PR China, 230009"]},{"name":"Hefei University of Technology , , 193 Tunxi Road , , ,","place":["Hefei, Anhui, PR China, 230009"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Si-Jie","family":"Wu","sequence":"additional","affiliation":[{"name":"Hefei University of Technology , , 193 Tunxi Road , , ,","place":["Hefei, Anhui, PR China, 230009"]},{"name":"Hefei University of Technology , , 193 Tunxi Road , , ,","place":["Hefei, Anhui, PR China, 230009"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ran","family":"Feng","sequence":"additional","affiliation":[{"name":"Hefei University of Technology , , 193 Tunxi Road , , ,","place":["Hefei, Anhui, PR China, 230009"]},{"name":"Hefei University of Technology , , 193 Tunxi Road , , ,","place":["Hefei, Anhui, PR China, 230009"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6618-8913","authenticated-orcid":true,"given":"Bao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Hefei University of Technology , , 193 Tunxi Road , , ,","place":["Hefei, Anhui, PR China, 230009"]},{"name":"Hefei University of Technology , , 193 Tunxi Road , , ,","place":["Hefei, Anhui, PR China, 230009"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,26]]},"reference":[{"key":"2026100711073132100_cit1","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1016\/j.semcdb.2016.12.001","article-title":"Extracellular vesicle mimetics: Novel alternatives\nto extracellular vesicle-based theranostics, drug delivery, and vaccines","volume":"67","author":"Kim","year":"2017","journal-title":"Semin. 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