Activated T-cell membrane-derived nanocargoes displaying multi-immune checkpoints for enhanced cancer immunotherapy.

The advent of immune checkpoint inhibitors (ICIs) has significantly transformed the landscape of cancer treatment in the last decade. However, the efficacy of single-agent ICI remains constrained due to multiple immune checkpoints (ICs)-mediated T cell suppression and inadequate T cell tumor infiltration. Here, we developed a novel approach using activated T-cell membrane-guided nanocarriers to simultaneously block multiple ICs and enhance T-cell infiltration. Initially, primary T cell activation was induced in vitro, and T cells with high expression of ICs were selected to prepare T-cell membrane vesicles. These vesicles were then utilized to coat immunogenic inducer-loaded liposomes (dLNPs) to create nanocarriers termed AM-dLNPs. The AM-dLNPs were demonstrated to effectively inhibit multiple ICs pathways through competitive blockade of immune checkpoint ligand-receptor interactions and down-regulation of immune checkpoint ligand expression. Additionally, the AM-dLNPs exhibited a strong ability to promote intratumoral T cell infiltration through targeted delivery of the immunogenic inducer. Benefiting from the exceptional biosafety profile, multi-ICs blockade efficacy, and tumor-targeting properties of the T-cell membrane vesicles, administration of AM-dLNPs resulted in a significant reduction in tumor progression and notable survival advantages in various mouse tumor models. These findings provide a basis for the clinical assessment of activated T-cell membrane-derived nanocarriers, which solves the dilemma of limited effects of ICI treatment without biosafety concerns. Its versatility also enables the targeted delivery of other immunogenic agents for synergistic antitumor immunotherapies.