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Long-term antigen stimulation often leads to exhaustion of CD8+ T cells, thereby weakening the efficacy of immunotherapy. To address this challenge, we developed Janus nanomotors (PML@fmPt NMs) constructed through cell membrane phase separation, providing an effective strategy for dynamic immune regulation. Unlike traditional nanoparticle manufacturing, negatively charged metal nanoparticles induce spontaneous gel-fluid domain separation on the membrane, generating a stable Janus structure with inherent asymmetry, modularity, and enhanced diffusion and migration rate. This biomimetic design enables inflammatory chemotaxis to act simultaneously on spleen and tumor tissues, achieving selective targeting of T cells and tumor cells. The nanomotors co-deliver metformin and CRISPR/Cas9, synergistically reversing T cell exhaustion and disrupting tumor tryptophan metabolism, which is a dual regulation concept called dual-output gear (DOG) therapy. In preclinical studies, this platform improved the mitochondrial respiratory capacity of CD8+ T cells and significantly inhibited tumor growth. In addition to therapeutic effects, this work also laid the blueprint for intelligent nanomotors based on biomaterials, highlighting the potential of phase separation engineering in the fabrication of next-generation nanomaterials: modular Janus configurations facilitate simplification of customization, enhance compatibility by using natural membranes, and the phase separation principle can be widely applied to other delivery systems. This research was published in ACS Nano under the title "Phase-Separation Engineered Nanomotors Enable Spleen-Tumor Dual Targeting to Reverse T-Cell Exhaustion".
References: DOI: 10.1021/acsnano.5c20175
