Lotus seedpod-inspired crosslinking-assembled hydrogels based on gold nanoclusters for synergistic osteosarcoma multimode imaging and therapy

Osteosarcoma is difficult to be resected through surgical operations without damage to the bone matrix, while chemotherapy and radiotherapy induce inevitable systemic injury. It is still a major challenge to develop a novel treatment suitable for the complex anatomical structure of the bone. Herein, inspired by lotus seedpods, injectable hydrogels with long-term retention for synergistic osteosarcoma treatment were developed. Gold nanoclusters (GNCs) with strong fluorescence (FL) and computed tomography (CT) imaging effects represented the lotus seeds. The oxidized hyaluronic acid (HA-ALD) chain resembled the stem. HA-ALD and GNCs form crosslinking-assembled hydrogels abbreviated as HG-CAHs through dynamic amide bonds. Compared with DNA-, pH-, and light-mediated assembly, this in situ method induces enhanced photothermal therapy (PTT) ability, ensures high biocompatibility, and retains the imaging function of GNCs, which contribute to lighting up osteosarcoma persistently for further diagnosis and treatment. In addition, the HG-CAHs with outstanding mechanical properties are similar to the lotus seedpods with supportive force and a typical porous structure. They are favorable for the local pH- and near-infrared (NIR)-responsive release of doxorubicin (Dox) owing to the acidic osteosarcoma microenvironment and the Brownian movement. The HG-CAHs ablate osteosarcoma efficiently and reduce metabolic toxicity significantly, which will aid in the development of a new generation of osteosarcoma treatments.