Background <p>Inflammatory arthritis (IA) is a group of chronic progressive inflammatory diseases characterized by the destruction of joints. The clinical efficacy and safety of the current drugs for patients with IA still need improvement, suggesting the importance of developing new therapeutic agents with the potential to specifically target inflammatory sites and precisely intervene in pathogenic molecules.</p> Results <p>Previously, we demonstrated that elevated PIM1 expression in CD4⁺ T cells could serve as a therapeutic target for IA. Herein, we constructed the neutrophil membrane-coated and MMP2-cleaved peptide-linked nanoparticles (NM@MRP-NP) to specifically deliver PIM1 inhibitor to CD4⁺ T cells in inflamed joints. In vitro experiments showed that NM@MRP-NP was a structurally defined, biologically stable nanotherapeutic system with efficient drug loading, which could be successfully deliver AZD1208, the PIM1 inhibitor, to activated CD4⁺ T cells upon exposure to MMP2. Besides, NM@MRP-NP effectively inhibited the differentiation of Th17 cell and suppressed the secretion of Th17-associated pathogenic cytokines in the presence of MMP2. In terms of mechanism, NM@MRP-NP regulates mitochondrial enzyme activity, including PDH, KGDH, and ATPase, through mito-Ca²⁺ influx, therefore accelerating OXPHOS to promote Th17 cell differentiation. In vivo assays determined that NM@MRP-NP specifically targeted the inflammatory joints of the SKG mice, a murine model of IA featuring disordered T cells, and then exhibited outstanding therapeutic effects on SKG mice through suppressing Th17 cells response under the condition of ensuring safety.</p> Conclusion <p>These results suggested that NM@MRP-NP was a structurally defined, biologically stable, inflammatory-targeted and conditionally releasing nanotherapeutic system with efficient drug delivery, which could provide new insight into the targeted interventions for IA.</p> Graphical abstract <p></p>