Smart Tumor Microenvironment‐Responsive Nanotheranostic Agent for Effective Cancer Therapy

The tumor microenvironment (TME), which includes acidic and hypoxic conditions, severely impedes the therapeutic efficacy of antitumor agents. Herein, MnO2‐loaded, bovine serum albumin, and PEG co‐modified mesoporous CaSiO3 nanoparticles (CaM‐PB NPs) are developed as a nanoplatform with sequential theranostic functions for the engineering of TME. The MnO2 NPs generate O2 in situ by reacting with endogenous H2O2, relieving the hypoxic state of the TME that further modulates the cancer cell cycle status to S phase, which improves the potency of co‐loaded S phase‐sensitive chemotherapeutic drugs. After the hypoxia relief, CaM‐PB can sustainably release drugs due to the enlarged pores of mesoporous CaSiO3 in the acidic TME, preventing the drug pre‐leakage into the blood circulation and insufficient drug accumulation at tumor sites. Moreover, the Mn2+ released from the MnO2 NPs at tumor sites can potentially serve as a diagnostic agent, enabling the identification of tumor regions by T1‐weighted magnetic resonance imaging during therapy. In vivo pharmacodynamics results demonstrate that these synergetic effects caused by CaM‐PB NPs significantly contribute to the inhibition of tumor progression. Therefore, the CaM‐PB NPs with sequential theranostic functions are a promising system for effective cancer therapy. An MnO2‐loaded, poly(ethylene glycol) and bovine serum albumin co‐modified mesoporous CaSiO3 nanoparticle (CaM‐PB) is developed for the engineering of the tumor microenvironment (TME). CaM‐PB can sequentially relieve the hypoxic state of the TME, tune cancer cell cycle to S phase, and sustainably release S phase‐sensitive drugs for improved cancer therapy, simultaneously providing a TME‐responsive magnetic resonance imaging for real‐time monitoring.