Tumor Membrane Based Delivery System Encapsulating Metfornin and TPP1 Peptide for Tumor Immune Therapy

Conventional cancer treatments face significant limitations, prompting the exploration of immune combination therapies targeting immune checkpoints as a means to overcome these challenges. The PD-1/PD-L1 signaling pathway plays a crucial role in tumor proliferation and immune evasion. TPP1, a peptide inhibitor targeting PD-L1, effectively blocks this pathway and suppresses tumor growth. Metformin has been shown to inhibit cancer cell proliferation, migration, and invasion while inducing apoptosis and inhibiting the expression of PD-L1. To leverage the synergistic therapeutic effects of TPP-1 and metformin, we designed and constructed a peptide-small molecule drug delivery system using tumor cell membranes. First, nanoscale tumor cell membrane vesicles were prepared via hypotonic ultrafiltration and coupled with the TPP1 peptide through co-incubation to form TPP1-cell membrane complexes. Simultaneously, mesoporous silica nanomaterials were synthesized and loaded with metformin by using the sol-gel method. Finally, the two components were mixed and sonicated to create the final drug delivery system. Both in vitro and in vivo experimental results demonstrated that this tumor cell membrane-based drug delivery system significantly prolonged the half-life of TPP1, maintained its ability to activate T cells and promote IFN-γ secretion, and effectively inhibited tumor growth. Our constructed nanodelivery system could provide a promising therapeutic platform for co-delivery of peptides and small-molecule inhibitors in cancer therapy.