Neutrophil-mediated delivery of paclitaxel and Bcl-2 siRNA reverses chemoresistance in bone-metastatic triple-negative breast cancer

Triple-negative breast cancer (TNBC) bone metastasis remains a significant clinical challenge owing to limited drug across the blood - bone marrow barrier as well as the chemotherapy resistance. Overexpression of the anti-apoptosis protein B-cell lymphoma-2 (Bcl-2) and activation of ATP-binding cassette transporter-mediated drug efflux pathway contribute substantially to paclitaxel (PTX) resistance, leading to poor therapeutic outcomes. Herein, we developed a biomimetic bone-targeted nanotherapeutic by integrating neutrophil “hitchhiking” technology with hyaluronic acid (HA)-modified lipid nanoparticles co-loaded with PTX and Bcl-2 small interfering RNA (siRNA) (BP-HLNP@NEs) for the therapy of TNBC bone metastasis. Leveraging neutrophil-mediated bone marrow homing and HA-CD44 receptor-mediated active targeting, BP-HLNP@NEs efficiently traversed the blood-bone marrow barrier, enhanced accumulation within metastatic bone lesions, and reduced off-target toxicity in the liver and spleen. Following cellular internalization, the co-delivered PTX and Bcl-2 siRNA synergistically suppressed tumor growth by silencing Bcl-2 expression, inhibiting the NF-κB/P-glycoprotein resistance pathway, restoring chemosensitivity, and activating caspase-mediated apoptosis. In orthotopic bone metastatic TNBC models, BP-HLNP@NEs markedly inhibited tumor progression, reduced secondary lung metastasis, preserved bone architecture, and elicited antitumor immune responses. Collectively, this biomimetic delivery platform overcomes both biological delivery barriers and chemoresistance, providing a promising therapeutic strategy for the treatment of TNBC bone metastasis.