Transforming cisplatin into targeted photothermal chemotherapeutics through the platinum-phosphate coordination within a hyaluronan nanogel

Cisplatin's (Cis's) antitumor efficacy is limited by dose-dependent toxicity due to nonspecific tissue distribution. While targeted Cis delivery and combination therapies boost therapeutic efficacy, developing multifunctional yet simplified formulations remains challenging. Inspired by the Cis's interaction with DNA, here, we transformed Cis into a reversible photothermal agent through the platinum-phosphate (Pt-phos) interaction within a hyaluronan (HA) nanogel (named as HA/PtP) to afford synergistic photothermal therapy (PTT) and chemotherapy. The HA/PtP nanogel exhibits near infrared absorption and 32.08% photothermal conversion efficiency, and degrades to release Cis through the reversible Pt-phos interaction under acidic conditions. Leveraging HA's intrinsic CD44 targeting, HA/PtP nanogel simultaneously enables highly efficient PTT and targeted chemotherapy in 4T1 breast tumor xenografts. Moreover, HA/PtP-based PTT successfully mimics hyperthermic intraperitoneal chemotherapy (HIPEC) but with alleviated Cis toxicity in MC38 metastatic mouse model. This HA/PtP nanogel represents a rationally designed Cis nanomedicine integrating the PTT with self-targeting and facile preparation.