NIR-light-controlled G-quadruplex hydrogel for synergistically enhancing photodynamic therapy via sustained delivery of metformin and catalase-like activity in breast cancer

Severely hypoxic condition of tumour represents a notable obstacle against the efficiency of photodynamic therapy (PDT). While mitochondria targeted therapy by metformin has been considered as a promising strategy for reducing oxygen consumption in tumours, its low treatment sensitivity, short half-life and narrow absorption window in vivo remain the intractable challenges. In this report, 5′-guanosine monophosphate (5′GMP), indocyanine green (ICG), hemin and metformin, were combined to construct a smart G-quadruplex (G4) hydrogel named HMI@GEL for breast cancer (BC) treatment. Benefiting from the photothermal (PTT) effect of ICG, HMI@GEL exhibited excellent characteristics of NIR-light-triggered and persistent drug delivery to maintain high intratumoral concentration of metformin. Furthermore, drug loading concentration of metformin reached an amazing 300 ​mg ​mL−1 in HMI@GEL. To our knowledge, it might be the highest loading efficiency in the reported literatures. With the combination of catalase-mimicking Hemin@mil88, metformin could inhibit tumour mitochondrial respiratory significantly, which sequentially permitted in situ efficient oxygen generation. Remarkable apoptosis and necrosis were achieved by the combination of PTT and synergistically enhanced PDT as well as the activated tumour immunotherapy. Collectively, the HMI@GEL in situ injectable platform showed a promising strategy for enhanced PDT by metformin, and opened new perspectives for treating BC versatilely.