Fig. 1: Design and mechanism of PGN_4.9 nanoadjuvant for reprogramming M2-like TAMs into M1 phenotype via pH-gated regulation of lysosomal function.

a Development of pH-gated nanoadjuvant for activatable cancer immunotherapy in response to lysosomal acidity of M2-like TAMs. b Engineered nanoadjuvant can selectively target M2-like TAMs in tumour tissues after intravenous injection. c Upon endocytosis, nanoadjuvant is dissociated into polymer-GFLG-IMDQ conjugates unimer in the highly acidic lysosomes (pH_L ~4.4) of M2-like TAMs, whereas keeps integrity in moderate acidic lysosomes (pH_L ~5.2) of other cells, including M0-, M1-like macrophages, tumour cells, and normal cells. The highly expressed lysosome proteases in M2-like TAMs will cleave the conjugates, followed by the efficient release of IMDQ, which activates the toll-like receptors 7/8 located in endo-lysosomes. By specific stimulation of TLR7/8 signalling, M2-like TAMs can be reprogrammed into M1-like phenotype with typical characteristics, including attenuated lysosomal acidity, decreased cathepsin activity, antigenic peptide preservation, and improved antigen cross-presentation for robust cancer immunotherapy. In contrast, PGN_4.9 nanoadjuvant keeps inert in other cell types within healthy tissues and circumvents acute systemic toxicity.