Charge-Reversal Polymer Nano-modulators for Photodynamic Immunotherapy of Cancer.

Nanomedicine offers an effective way to regulate the balance between cytotoxic T lymphocytes (CTLs) and suppressive regulatory T lymphocytes (Tregs), which however has been rarely exploited for cancer immunotherapy. We herein report a charge-reversal polymer nano-modulator (SPDMCN) activated by tumor microenvironment (TME) for photodynamic immunotherapy of cancer. SPDMCN is constructed by conjugating an immunomodulator (demethylcantharidin, DMC) to the side chains of a photodynamic polymer via an acid-liable linker. The negative charge of SPDMCN ensures its high stability in blood circulation and ideal tumor accumulation; while the later exposure to acidic TME reverses its surface charge to positive, enhancing its tumor penetration and locally releasing DMC. Upon near-infrared photoirradiation, SPDMCN generates singlet oxygen to ablate tumor and promote maturation of dendritic cells. Concurrently, the released DMC inhibits PP2A activity and decreases Tregs differentiation. Such combinational action induces a sharp increase in CTL/Treg ratio in TME and effectively inhibits both primary and distant tumors in living mice.