Multifunctional hyaluronic acid-modified hollow MnO(2) nanoplatform co-delivering with L-Arginine and Regorafenib for synergistic therapy against colorectal cancer.

The high rates of recurrence and metastasis in colorectal cancer (CRC), coupled with its immunosuppressive tumor microenvironment (TME), severely constrain patient survival. To overcome the limitations of monotherapies, this study developed a multifunctional targeted nanoplatform (RLHMnH). This system consists of a hyaluronic acid (HA)-modified hollow manganese dioxide (H-MnO2) nanocarrier co-loaded with the anti-angiogenic drug Regorafenib (Reg) and the nitric oxide precursor L-Arginine (L-Arg) for synergistic triple therapy against CRC. The platform leverages HA-mediated CD44 receptor targeting to achieve enhanced tumor accumulation.

Within the TME, the H-MnO2 framework undergoes rapid responsive decomposition. On one hand, Within the acidic and GSH-rich TME, H-MnO2 undergoes reductive degradation to release Mn2+, concomitantly depleting GSH and disrupting redox homeostasis. The released Mn2+ further catalyzes Fenton-like conversion of endogenous H2O2 into highly cytotoxic ·OH, thereby inducing oxidative damage and tumor cell apoptosis. On the other hand, the concomitantly released Reg effectively blocks tumor angiogenesis by inhibiting the VEGFR2 signaling pathway, while L-Arg generates nitric oxide, synergistically reversing drug resistance, alleviating hypoxia, and activating anti-tumor immunity.

Both in vitro and in vivo experiments demonstrated that RLHMnH, through integrating the triple synergistic mechanisms of CDT, anti-angiogenesis, and gas therapy, achieved a remarkable tumor inhibition rate of ∼75% in a CT26 xenograft model and potently suppressed CT26 cell viability to below 20% at 72 h, showcasing significant suppression of CRC.

This study provides an innovative nano-carrier-based synergistic strategy to overcome the current therapeutic bottlenecks in CRC treatment.