Synergistic Programming of Macrophages by Hybrid Glycocalyx-Inspired Nanoparticles for Adoptive Cell Therapy

Adoptive cell transfer has emerged as a promising approach for cancer immunotherapy. However, the transfer of macrophages is limited by their high plasticity, which can switch the pro-inflammatory phenotype (M1-like) to the anti-inflammatory state (M2-like) in an immunosuppressive microenvironment. Inspired by natural glycocalyx and its indispensable functions on immune response and communication, here we report an approach of hybrid glycocalyx-inspired nanoparticles that integrates (oligo)mannoside-modified glycopolymers with iron oxide to program primary macrophages into a persistent M1-like phenotype in which glycocalyx-inspired nanoparticles and iron oxide act as the extracellular and intracellular stimulatory signals, respectively. Importantly, with the synergistically enhanced immunoactivation of dual signals, the programmed macrophages are able to resist the immunosuppressive microenvironment and exhibit significantly enhanced tumoricidal effects both in vitro and in vivo. We further demonstrate that adoptive transfer of macrophages programmed by hybrid glycocalyx-inspired nanoparticles also improves the tumor microenvironment and increases T cell responses. These results, using glycocalyx mimetics as macrophage encoders, highlight an alternative approach for the development of adoptive cell immunotherapies.