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Herein, mitochondrial targeting is introduced in PDT of RA to implement a \u201cless\u2010is\u2010more\u201d strategy, where higher apoptosis in pro\u2010inflammatory cells are achieved with lower laser power. In arthritic rats, chlorine 6\u2010loaded and mitochondria\u2010targeting liposomes (Ce6@M\u2010Lip) passively accumulated in inflamed joints, entered pro\u2010inflammatory macrophages, and actively localized to mitochondria, leading to enhanced mitochondrial dysfunction under laser irradiation. By effectively disrupting mitochondria, pro\u2010inflammatory macrophages are more susceptible to PDT, resulting in increased apoptosis initiation. Additionally, it identifies that high\u2010power irradiation caused cell rupture and release of endogenous danger signals that recruited and activated additional macrophages. In contrast, under low\u2010power irradiation, mitochondria\u2010targeting Ce6@M\u2010Lip not only prevented inflammation but also reduced pro\u2010inflammatory macrophage infiltration and pro\u2010inflammatory cytokine secretion. Overall, targeting mitochondria reconciled therapeutic efficacy and inflammation, thus enabling efficacious yet inflammation\u2010sparing PDT for RA. This highlights the promise of mitochondrial targeting to resolve the dilemma between anti\u2010inflammatory efficacy and inflammatory exacerbation in PDT by implementing a \u201cless\u2010is\u2010more\u201d strategy.<\/jats:p>","DOI":"10.1002\/smll.202307261","type":"journal-article","created":{"date-parts":[[2024,1,15]],"date-time":"2024-01-15T23:47:25Z","timestamp":1705362445000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["A Less\u2010is\u2010More Strategy for Mitochondria\u2010Targeted Photodynamic Therapy of Rheumatoid Arthritis"],"prefix":"10.1002","volume":"20","author":[{"given":"Qingting","family":"Zuo","sequence":"first","affiliation":[{"name":"Key laboratory of Drug Targeting and Drug Delivery System (Ministry of Education) West China School of Pharmacy Sichuan University  No. 17, Block 3, South Renmin Road Chengdu 610041 P.R. 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