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

ABSTRACT 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.