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.