Enzyme-Instructed Peptide Self-Assembly as A Cell Membrane Lichen Activating Macrophage-Mediated Cancer Immunotherapy

Abstract

Abstract Targeted immunomodulation for reactivating innate cells, especially macrophages, holds great promise to complement current adaptive immunotherapy. Nevertheless, there is still a lack of high-performance inhibitors for blocking macrophage phagocytosis checkpoints in immune quiescent solid tumors so far. Herein, a peptide-antibody combo-supramolecular in situ assembled CD47 and CD24 bi-target inhibitor (PAC-SABI) is described, which undergoes biomimetic surface propagation like lichens on cancer cell membranes through ligand-receptor binding and enzyme-triggered reactions. Primarily, the PAC-SABIs demonstrate specific avidity for the overexpressed CD24 on the cancer cell surface with anti-CD24 monoclonal antibody (mAb). Subsequently, they exhibit alkaline phosphatase-catalyzed rapid dephosphorylation of phosphopeptides, constructing a three-dimensional nanofiber network and reinstating blockade of CD47 signaling. By concurrent inhibition of CD47 and CD24 signaling, PAC-SABIs stimulate macrophage phagocytosis and initiate T cell antitumor response. Remarkably, compared with anti-CD24 mAb, PAC-SABIs enhance the phagocytic ability of macrophages by 3–4 times in vitro and in vivo while facilitating infiltration of CD8+ T cells into 4T1 tumors. Moreover, combining PAC-SABIs with anti-PD-1 therapy effectively suppressed 4T1 tumor growth in murine models, surmounting other treatment groups with a 60-day survival rate of 57%. The in vivo construction of PAC-SABI-based nanoarchitectonics provides an efficient platform for bridging innate and adaptive immunity to maximize therapeutic potency.