{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T02:21:25Z","timestamp":1791253285662,"version":"4.1.0"},"reference-count":89,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T00:00:00Z","timestamp":1774828800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background: Acute Lung Injury\/Acute Respiratory Distress Syndrome (ALI\/ARDS) is a fatal inflammatory disorder driven by M1 macrophages and the associated inflammatory cascade. Targeted drug delivery to these cells is a promising therapeutic strategy. Methods: L-arginine was conjugated to chitosan of different molecular weights. The resulting curcumin nanocrystals (Arg-CS-Cur) were characterized for conjugation efficiency, zeta potential, stability, and drug release profile. Cellular uptake mechanisms and mitochondrial targeting were investigated in lipopolysaccharide (LPS)-induced M1 macrophages using specific endocytic inhibitors and confocal microscopy. Results: Low-molecular-weight chitosan (MW 50 kDa) showed the highest L-Arg conjugation efficiency (22.31%). The optimized Arg-CS-Cur nanocrystals exhibited high zeta potential (\u00b147.5 mV), excellent stability, and a superior drug release. They were internalized by M1 macrophages more efficiently than unmodified CS-Cur or free curcumin (p &lt; 0.05). Uptake occurred via clathrin-mediated endocytosis (p &lt; 0.001) and was mediated by CAT-2, which was highly expressed in M1 macrophages (p &lt; 0.001). Arg-CS-Cur specifically targeted the mitochondria, reducing ROS and NLRP3 expression, thus inhibiting the NLRP3 inflammasome pathway (p &lt; 0.001). Conclusions: This L-arginine-modified chitosan-based nanodelivery system synergistically exploits CAT-2 and clathrin pathways to deliver curcumin to M1 macrophage mitochondria, inhibiting the NLRP3 inflammasome. This dual-targeted strategy offers a promising approach for treating ALI\/ARDS.<\/jats:p>","DOI":"10.3390\/pharmaceutics18040425","type":"journal-article","created":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T13:41:53Z","timestamp":1774878113000},"page":"425","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["L-Arginine-Modified Chitosan Curcumin Nanocrystals Target M1 Macrophages via CAT-2\/Clathrin-Mediated Endocytosis for Mitochondrial Protection and ALI\/ARDS Therapy"],"prefix":"10.3390","volume":"18","author":[{"given":"Xiaowen","family":"Yang","sequence":"first","affiliation":[{"name":"School of Chinese Materia Medica, Beijing University of Chinese Medicine, Yang Guang South Street, Fang-Shan District, Beijing 102488, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-5175-7199","authenticated-orcid":false,"given":"Shiyue","family":"Wu","sequence":"additional","affiliation":[{"name":"School of Chinese Materia Medica, Beijing University of Chinese Medicine, Yang Guang South Street, Fang-Shan District, Beijing 102488, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiya","family":"Dou","sequence":"additional","affiliation":[{"name":"School of Chinese Materia Medica, Beijing University of Chinese Medicine, Yang Guang South Street, Fang-Shan District, Beijing 102488, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxiao","family":"Dong","sequence":"additional","affiliation":[{"name":"School of Chinese Materia Medica, Beijing University of Chinese Medicine, Yang Guang South Street, Fang-Shan District, Beijing 102488, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4576-2618","authenticated-orcid":false,"given":"Jundong","family":"Dai","sequence":"additional","affiliation":[{"name":"Department of Chinese Medicinal Pharmaceutics, Beijing University of Chinese Medicine, Yang Guang South Street, Fang-Shan District, Beijing 102488, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"275","DOI":"10.3109\/01902148.2013.808285","article-title":"Upregulation of miR-146a contributes to the suppression of inflammatory responses in LPS-induced acute lung injury","volume":"39","author":"Zeng","year":"2013","journal-title":"Exp. 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