Rigid nanoparticles for efficient tumor immunotherapy through mechanical force mediated reprogramming of tumor-associated macrophages

The enrichment of M2-phenotype tumor-associated macrophages (TAMs) is the main factor to create an immunosuppressive microenvironment, which seriously attenuates antitumor treatment. Herein, we explored the capability of rigid nanoparticles to reprogram TAMs to the M1-like phenotype via mechanical force. We designed and synthesized amphiphilic copolymer PLA-b-PItEG initiated by the HO-Pd(II) complex. In contrast to polyethylene glycol, the hydrophilic PItEG segments have a helical conformation, which endows the self-assembled PLA-b-PItEG nanoparticles with stiff surface characteristics of higher Young's modulus and hydrophobicity. The rigid nanoparticles displayed strong interaction with TAMs to produce greater deformation of cell membrane and activated mechanosensitive potassium ion channel. Consequently, rigid nanoparticles exerted a positive effect on the proinflammatory polarization of TAMs. The expression level of CD86, a typical M1 macrophage marker, was increased by 60% compared with that in the soft PEG-NP group while CD206, a typical M2 macrophage marker, was decreased. Furthermore, several M1-related cytokines such as TNF-α, IL12p40, IL-6 and IL-1β were upregulated. In vitro and in vivo immune responses triggered by rigid nanoparticles could significantly inhibit B16F10 tumor growth with 71.44% tumor inhibitory rate. This study offers new insight into the use of mechanical forces for tumor immunotherapy.