Metformin Mediated Pd-L1 Downregulation In Combination With Photodynamic-Immunotherapy For Treatment Of Breast Cancer

Intelligent nanomaterials open up new avenues for realizing safer and more effective combination immunotherapy. Herein, a kind of simple enzymatically cleavable self-delivery nanoparticles (MA-pepA-Ce6 NPs) is developed by conjugating acidic-sensitive small-molecule programmed cell death ligand 1 (PD-L1) inhibitor (Metformin, MET) with photosensitizer (chlorin e6, Ce6) through matrix metalloproteinase-2 (MMP-2) cleavable peptide (GPLGVRGDK, pepA). Noticeably, these self-delivery peptide-based NPs can circumvent the controversial biosafety facing nanomaterials. Moreover, MA-pepA-Ce6 NPs are degraded by overexpressed MMP-2 in tumor microenvironment (TME) and expose the VRGDK-Ce6. The exposed VRGDK-Ce6 shows superior targeting ability towards integrin alpha(v)beta(3) receptor, ensuring sufficient accumulation and laser-activated robust antitumor immune effects. Remarkably, the released MET in tumor microenvironment hampers the PD-L1 expression and augments the antitumor immune response elicited by photodynamics therapy (PDT), thus significantly improving therapeutic outcomes. Overall, this study offers a potential appealing paradigm of synergistic PDT-triggered immunotherapy by revealing MET-mediated PD-L1 downregulation to achieve tumor eradication.