Mechano-reprogramming of tumor-associated macrophages by engineering nanogel stiffness for suppression of tumor development

Nanoparticle mechanical properties, as critical factors in tumor targeting drug delivery, have recently been revealed to regulate cellular biological functions. While macroscopic mechanical stimuli are demonstrated to reprogram tumor-associated macrophages (TAMs), it is unclear how TAMs respond to microscopic stimuli from nanoparticles. Herein, we demonstrated that the stiff 15%NGs presented stronger interactions with integrin than the soft 2%NGs, promoting the polymerization of actin and the activation of yes-associated protein 1. Therefore, the pro-inflammatory phenotype of TAMs was enhanced and the secretion of tumor necrosis factor α was increased. In synergy with high liver enrichment, 15%NGs exhibited superior tumor suppression by reprogramming TAMs in orthotopic liver tumors. Crucially, the pro-inflammatory phenotype of macrophages reprogrammed by 15%NGs significantly induced the apoptosis of tumor cells in ex vivo hepatocellular carcinoma tissues from patients. This study proposes a mechanical signaling pathway to reprogram TAMs by manipulating nanogel stiffness and provides new insights for rational design of cancer nanomedicines.