Endo/exo-genous dual-stimuli responsive gold nanotetrapod-based nanoprobe for magnetic resonance imaging and enhanced multimodal therapeutics by amplifying·OH generation

Tumor microenvironment (TME) responsive chemodynamic therapy (CDT) can produce high-toxic hydroxyl radicals (·OH) to kill cancer cells, but the limited concentration of endogenous hydrogen peroxide (H₂O₂) seriously restricted its application. Herein, using endo/exo-genous dual-stimuli, a novel nanoprobe with enhanced ·OH generation was developed for magnetic resonance (MR) imaging and multimodal therapeutics, in which gold nanotetrapod (AuNTP) with photothermal therapy (PTT) performance was coated with mesoporous silica (mSiO₂) and loaded with cisplatin (CDDP), then a thin layer of manganese dioxide (MnO₂) was deposited to construct AuNTP@mSiO₂@CDDP@MnO₂ nanoprobes. In TME, endogenous H₂O₂, CDDP-triggered self-supplying H₂O₂ produced via cascade reaction and the exogenous photothermal effect of AuNTPs together enhanced the ·OH generation of Mn²⁺ induced by glutathione (GSH) responsive degradation of MnO₂. The prepared AuNTP@mSiO₂@CDDP@MnO₂ nanoprobes possessed perfect core@shell structure, good biocompatibility and GSH-dependent MR performance, in which the relaxation rates increased from 0.717 mM^-1·s^-1 to 8.12 mM^-1·s^-1. Under the multimodal therapeutics of CDT/PTT/chemotherapy, the developed AuNTP@mSiO₂@CDDP@MnO₂ nanoprobes demonstrated good antitumor efficacy. Our work provided a promising strategy for constructing TME-responsive nanoprobes with endo/exo-genous stimuli, achieving enhanced visualized theranostics of tumors. STATEMENT OF SIGNIFICANCE: Tumor microenvironment (TME) responsive chemodynamic therapy (CDT) can produce high-toxic hydroxyl radicals (·OH) to kill cancer cells, but the limited concentration of endogenous hydrogen peroxide (H₂O₂) seriously restricted its application. Using endo/exo-genous dual-stimuli, AuNTP@mSiO₂@CDDP@MnO₂ (AMCM) nanoprobe was constructed, in which endogenous H₂O₂, CDDP-triggered self-supplying H₂O₂ and the exogenous photothermal effect of AuNTPs together enhanced the ·OH generation. Under the multimodal therapeutics of CDT/PTT/chemotherapy, the developed AuNTP@mSiO₂@CDDP@MnO₂ nanoprobe demonstrated good antitumor efficacy, and provided a promising strategy for constructing TME-responsive nanoprobes with endo/exo-genous stimuli, achieving enhanced CDT of tumors.