Antagonistic peptide-displayed artificial exosome carrying PROTAC for the synergistic lung cancer therapy

The present lung cancer therapy encounters the difficulties including surgical trauma, drug resistance, or immune exhaustion. Increasing evidences also indicated that the monotherapy showed limited effects in lung cancer therapy. Here, we have developed a type of combination therapy system (HELD), which is constructed by encapsulating the proteolysis targeting chimeras (PROTAC) reagent targeting to Bromodomain-containing proteins 4 (BRD4), dBET6 into Poly(lactic-co-glycolic acid) (PLGA) nanoparticles, and further coating them with hybrid exosome membranes-derived from lung cancer cells and programmed death-1 (PD-1) antagonist peptide-engineered HEK 293T cells. The PD-1 antagonist peptide (PD1A) on the surface of HELD can be cleaved in the matrix metallopeptidase 2 (MMP2)-abundant environments, which is beneficial for the potential immune checkpoint blockade. Moreover, the PROTAC-loaded nanoparticle can be uptaken by the lung cancer cells effectively via the homotypic targeting effects, and resulting in 89.2 ± 3.7% BRD4 protein degradation in these cells. HELD exhibited efficient tumor accumulation, powerful BRD4 degradation, and c-Myc suppression, thereby impairing tumor proliferation. Simultaneously, HELD enhanced CD8⁺ and CD4⁺ T cell infiltration, increased IFN-γ, IL-2, and TNF-α secretion, collectively remodeling the TME. In vivo, HELD mediated synergistic lung cancer therapy and achieved excellent tumor inhibition with minimal systemic toxicity. This study demonstrates that combining PROTACs and PD-1 antagonist peptides provides a promising therapeutic strategy for lung cancer.