Tumor intracellular self-assembled nanoparticles induced by bacteria elicited erythrocyte infiltration realize antitumor efficacy of zoledronate

Despite the promise of nanomedicines leveraging the enhanced permeability and retention (EPR) effect for tumor targeting, their clinical translation remains hindered due to physiological barriers, rapid clearance, and poor intratumoral diffusion. <i>In situ</i> self-assembly of nanomedicines within tumors offers a promising strategy to enhance tumor accumulation. However, significant challenges persist. Herein, our findings reveal that tumor-infiltrating erythrocytes demonstrate the capacity to endogenously synthesize self-assembled nanomedicine with clinically approved small-molecule drug. Attenuated <i>Salmonella Typhimurium</i> VNP20009 (VNP) can induce tumor-specific erythrocyte infiltration. Erythrocytes infiltrating the tumor site are phagocytosed by tumor cells and degraded into ferrous ions through the action of heme oxygenase. In the presence of zoledronic acid, ferrous irons interact with the zoledronic acid, resulting in the intracellular self-assembly of nanoparticles within tumor cells. These nanoparticles exhibit peroxidase-mimetic activity, and continuously catalyze the generation of reactive oxygen species (ROS) within the tumor, ultimately inducing tumor cell apoptosis. Therefore, this bioengineered therapeutic strategy that harnesses erythrocyte phagocytosis to drive tumor-specific intracellular self-assembly of peroxidase-mimetic nanoparticles may open up new nanotechnology for drug delivery and improve antitumor therapy.