A supramolecular self-assembled nanomaterial for synergistic therapy of immunosuppressive tumor

Triple negative breast cancer (TNBC) is an immunosuppressive "cold" tumor that lacks immune cell infiltration and activation, resulting in a poor response to immune checkpoint blockade (ICB) therapies. In addition, TNBC is poorly responsive to targeted therapies due to the absence of efficient molecular targets. A strategy that can block molecular signal transduction, stimulate immunogenicity, and activate the immune response is a promising approach to achieve ideal clinical benefit. Herein, we designed and synthesized an aggregation-induced emission luminogen (AIEgen)-conjugated self-assembling peptide that targets epidermal growth factor receptor (EGFR), named TPA-FFG-LA. TPA-FFG-LA peptides form nanoassemblies on the surface of EGFR-positive TNBC cells and are internalized into cells through endocytosis, which inhibit EGFR signaling transduction and provoke lyso-somal membrane permeabilization (LMP). Upon light irradiation, the aggregated AIEgens produce massive reactive oxygen species (ROS) to exacerbate LMP and trigger immunogenic cell death (ICD), resulting in elim-ination of residual EGFR-negative tumor cells and exerting long-term antitumor effects. The in vitro and in vivo experiments verified that TPA-FFG-LA nanoassemblies suppress tumor growth, provoke immune cell activation and infiltration, and cause EGFR degradation and LMP. These results suggest that the combination of supra-molecular assembly induced molecular targeting effects and lysosome dysfunction with ICD-stimulated immune activation is a plausible strategy for the efficient therapy of immunosuppressive TNBC.