Wei Li, Li Ge, Dan Zhong, Y X Zhang, Shihan Xiao, D. H. Zhang, Zizhen Liu, Zini Wen, Yi-Xiang Wang, Qin Chen, Yue Wang, Xiaodong Sun
ABSTRACT Triple‐negative breast cancer (TNBC) presents high heterogeneity, strong invasiveness, lack of clear molecular targets, and a propensity for immune evasion. Herein, a pH‐responsive, targeted nanoplatform—Veliparib@MnCl 2 PEG‐E5 nanoparticles (VMP NPs)—is developed for enhanced antitumor immune response via mechanotransduction. VMP NPs are constructed via self‐assembly of a poly (ADP‐ribose) polymerase (PARP) inhibitor (Veliparib) and Mn 2 + coordination core, and functionalized with a C‐X‐C chemokine receptor type 4 (CXCR4)‐targeting 1,2‐Distearoyl‐sn‐glycero‐3‐phosphoethanolamine‐polyethylene glycol‐E5 peptide shell. These NPs exhibit uniform particle size distribution, biocompatibility, stability, and efficient CXCR4‐mediated cellular uptake. They inhibit the proliferation and migration of MDA‐MB‐231 cells. In a co‐culture system with NK‐92 cells, VMP NPs enhance NK‐92 cell immune responses, increasing cytotoxicity and promoting the secretion of IFN‐γ, TNF‐α, perforin, and granzyme B, thereby activating the NK cell‐mediated extrinsic apoptotic pathway. Additionally, VMP NPs upregulate TNF‐related apoptosis‐inducing ligand (TRAIL) receptor 2 expression on MDA‐MB‐231 cells, sensitizing cells to TRAIL‐mediated apoptosis and activating the intrinsic apoptotic pathway synergistically. In a murine model of tumors, this coordinated mechanism enables efficient tumor targeting, marked growth suppression, and a pro‐inflammatory tumor microenvironment via mechanotransduction, with little detectable systemic toxicity. These findings illustrate the potential of this multifunctional nanoplatform as a promising and well‐tolerated strategy for targeted TNBC immunotherapy.