A Less‐is‐More Strategy for Mitochondria‐Targeted Photodynamic Therapy of Rheumatoid Arthritis

Abstract Conventional photodynamic therapy (PDT) of rheumatoid arthritis (RA) faces a dilemma: low‐power is insufficient to kill pro‐inflammatory cells while high‐power exacerbates inflammation. Herein, mitochondrial targeting is introduced in PDT of RA to implement a “less‐is‐more” strategy, where higher apoptosis in pro‐inflammatory cells are achieved with lower laser power. In arthritic rats, chlorine 6‐loaded and mitochondria‐targeting liposomes (Ce6@M‐Lip) passively accumulated in inflamed joints, entered pro‐inflammatory macrophages, and actively localized to mitochondria, leading to enhanced mitochondrial dysfunction under laser irradiation. By effectively disrupting mitochondria, pro‐inflammatory macrophages are more susceptible to PDT, resulting in increased apoptosis initiation. Additionally, it identifies that high‐power irradiation caused cell rupture and release of endogenous danger signals that recruited and activated additional macrophages. In contrast, under low‐power irradiation, mitochondria‐targeting Ce6@M‐Lip not only prevented inflammation but also reduced pro‐inflammatory macrophage infiltration and pro‐inflammatory cytokine secretion. Overall, targeting mitochondria reconciled therapeutic efficacy and inflammation, thus enabling efficacious yet inflammation‐sparing PDT for RA. This highlights the promise of mitochondrial targeting to resolve the dilemma between anti‐inflammatory efficacy and inflammatory exacerbation in PDT by implementing a “less‐is‐more” strategy.