Enhancing antitumor immunity in triple-negative breast cancer through reversal of T-cell exhaustion using a CD8-targeted and membrane-camouflaged nanocarrier delivering small interfering RNA against sorting Nexin 9.

T cell exhaustion (Tex) severely limits the efficacy of tumor immunotherapy, yet strategies targeting its upstream regulatory mechanisms remain underexplored. In this study, a targeted nanodelivery system, CD8a-RM-MOF@siSNX9, was developed to preferentially enrich siRNA delivery in CD8+ T cells and evaluate its potential to reverse Tex in triple-negative breast cancer (TNBC). Using a 4T1-induced TNBC mouse model combined with RNA sequencing analysis, SNX9 was identified as a key regulator associated with Tex. Silencing SNX9 was accompanied by reduced NFATc2-NR4A1-TOX signaling, decreased exhaustion phenotypes, and enhanced cytokine secretion and cytotoxic activity of CD8+ T cells. The nanoplatform exhibited prolonged circulation in vivo (t₁/₂ ≈ 12.4 h) and efficient tumor-targeted accumulation (~ 8.5%ID/g). Importantly, the nanoparticles preferentially accumulated in CD8+ T cells within the tumor microenvironment, leading to SNX9 knockdown, attenuation of the NFATc2-NR4A1-TOX regulatory program, reversal of Tex, and significant suppression of TNBC tumor growth while maintaining favorable biosafety. Collectively, these findings demonstrate that CD8a-RM-MOF@siSNX9 represents a promising targeted siRNA delivery platform with preferential CD8+ T-cell enrichment for targeting Tex and enhancing antitumor immunity in TNBC.