Hierarchical Targeting of TREM2 ⁺ Myeloid Cells via Acid‐Triggered OMVs Reprogram Immunosuppression and Suppress Osteolysis in Bone‐Metastatic TNBC

Triple-negative breast cancer (TNBC) bone metastasis is characterized by an immunosuppressive microenvironment dominated by triggering receptor expressed on myeloid cells 2 (TREM2) ⁺ myeloid cells, which promote osteoclastogenesis, as well as T cell exclusion. To disrupt myeloid-driven immunosuppression, we developed a hierarchical targeting nanoplatform (siTREM2@ETP-PEOz-OMVs) that exploits pH-responsive outer membrane vesicle (OMV) exposure for selective myeloid cell uptake in acidic TNBC bone metastatic microenvironment, enabling TREM2 silencing-driven macrophage repolarization and osteoclast inhibition to alleviate immunosuppression and block tumor progression. After achieving specific targeting of metastatic lesions through phage display-identified TNBC-targeting peptides, this nanoplatform utilizes the acidic tumor microenvironment (TME) to trigger pH-responsive dissociation of 2-ethyl-2-oxazoline (PEOz). The released OMVs subsequently leverage their inherent Toll-like receptor 4 (TLR4) affinity to achieve selective internalization by myeloid cells. TREM2 silencing repolarizes over 50% of macrophages to a proinflammatory phenotype, activates antitumor immunity via approximately twofold increased CD4⁺/CD8⁺ T cell infiltration, and inhibits over 70% of osteoclastogenesis, thereby achieving 79.5% suppression of osteolysis-mediated tumor progression. This strategy represents a novel approach for precise myeloid reprogramming in TNBC bone metastasis.