Molecular engineering of anti-PD-L1 peptide and photosensitizer for immune checkpoint blockade photodynamic-immunotherapy.

• Nanomedicne aiming to tackle the potential risk of ICB, e.g. irAEs was developed. • Molecular engineering strategy was used to precisely control the loading content of anti-PD-L1 peptide (APP). • The synthesized IR780-M-APP molecules obtained a precise loading content of 48.4 wt % APP and 20.2 wt % IR780 respectively. • IR780-M-APP NPs potently enhanced the tumor penetration of IR780 via an enzyme-responsive size change. • IR780-M-APP NPs integrating photodynamic immunotherapy with PD-L1 blocking successfully amplified the antitumor efficacy. Immune checkpoint blockade (ICB) strategy based on suppressing programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway has been proved to be promising and effective in cancer immunotherapy. However, its potential risk of immune-related adverse events (irAEs) places stringent requirements on the precise loading of anti-PD-L1 agent in nanomedicine. Precise control of the loading content of anti-PD-L1 antibody is a difficult task since physical encapsulation has inevitable drawbacks like batch-to-bath variation and chemical modification is limited by the low stability of the antibody. Herein, we proposed a molecular engineering strategy to develop the nanomedicine with precise control of anti-PD-L1 agent content by using anti-PD-L1 peptide (APP) as the substitute to anti-PD-L1 antibody. The APP was chemically bonded with a photosensitizer IR780 to obtain IR780-M-APP, a molecule able to self-assemble into nanoparticles (NPs) with a precise APP loading (48.4 wt%) determined by the molecular structure. Specifically, the IR780 moiety in IR780-M-APP NPs endows the nanoparticles with photodynamic therapeutic effect as well as the ability to trigger immunogenic cell death (ICD), while the APP moiety can block the PD-1/PD-L1 pathway for promoting immunotherapy. The proposed photodynamic-immunotherapy nanoplatform not only killed primary tumors directly but also eradicated the metastatic and invasive tumors effectively. The present molecular engineering strategy combined with anti-PD-L1 peptide might provide more opportunities for the design of advanced nanoplatforms for cancer therapy. [ABSTRACT FROM AUTHOR]