Platinum‐Coordinated Dual‐Responsive Nanogels for Universal Drug Delivery and Combination Cancer Therapy

Developing a universal nanoplatform for efficient delivery of various drugs to target sites is urgent for overcoming various biological barriers and realizing combinational cancer treatment. Nanogels, with the advantages of both hydrogels and nanoparticles, may hold potential for addressing the above issue. Here, a dual-responsive nanogel platform (HPC nanogel) is constructed using β-cyclodextrin-conjugated hyaluronic acid (HA-βCD), polyethyleneimine (PEI), and cisplatin. HA-βCD and PEI compose the skeleton of the nanogel, and cisplatin molecules provide the junctions inside the skeleton, thus affording a multiple interactions-based nanogel. Besides, HA endows the nanogel with hyaluronidase (HAase)-responsiveness, and cisplatin guarantees the glutathione (GSH)-responsive ability, which make the nanogel a dual-responsive platform that can degrade and release the loaded drugs when encountering HAase or GSH. Additionally, the HPC nanogel possesses excellent small-molecule drug and protein loading and intracellular delivery capabilities. Especially, for proteins, their intracellular delivery via nanogels is not hindered by serum proteins, and the enzymes delivered into cells still maintain their catalytic activities. Furthermore, the nanogel can codeliver different cargoes to achieve "cocktail" chemotherapeutic efficacy and realize combination cancer therapy. Overall, the HPC nanogel can serve as a multifunctional platform capable of delivering desired drugs to treat cancer or other diseases.