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 αvβ3 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. A new self‐delivery nanoparticle (MA‐pepA‐Ce6 NP) for co‐delivering a photosensitizer (chlorin e6) and small‐molecule programmed cell death ligand 1 (PD‐L1) inhibitor (Metformin) is constructed. Simple and biodegradable materials endow safety. Tumor microenvironment‐specific stimuli responses enable effective drug accumulation. More importantly, the combination of photodynamic therapy and PD‐L1 inhibition induces effective antitumor immune responses, indicating the potential application in cancer immunotherapy.