Bioorthogonal In Situ Polymerization of Dendritic Agents for Hijacking Lysosomes and Enhancing Antigen Presentation in Cancer Cells

A low-generation lysine dendrimer, SPr-G2, responds to intracellular glutathione to initiate bioorthogonal in situ polymerization, resulting in the formation of large assemblies in mouse breast cancer cells. The intracellular large assemblies of SPr-G2 can interact with lysosomes to induce lysosome expansion and enhance lysosomal membrane permeabilization, leading to major histocompatibility complex class I upregulation on tumor cell surfaces and ultimately tumor cell death. Moreover, the use of the SPr-G2 dendrimer to conjugate the chemotherapeutic drug, camptothecin (CPT), can boost the therapeutic potency of CPT. Excellent antitumor effects in vitro and in vivo are obtained from the combinational treatment of the SPr-G2 dendrimer and CPT. This combinational effect also enhances antitumor immunity through promoting activation of cytotoxic T cells in tumor tissues and maturation of dendritic cells. This study can shed new light on the development of peptide dendritic agents for cancer therapy. A low-generation dendritic agent is developed to cause lysosomal dysfunction and improve antigen presentation and antitumor immunity. The dendrimers undergo glutathione-mediated in situ polymerization and aggregation into large particles with a high positive charge, thereby causing lysosomal membrane permeabilization, enhanced major histocompatibility complex class I expression and camptothecin release, followed by dendritic cell maturation and cytotoxic CD8+ T cell activation. image