Biodegradable Metal-Organic-Framework-Gated Organosilica for Tumor-Microenvironment-Unlocked Glutathione-Depletion-Enhanced Synergistic Therapy

The clinical employment of cisplatin (cis-diamminedichloroplatinum(II) (CDDP)) is largely constrained due to the non-specific delivery and resultant serious systemic toxicity. Small-sized biocompatible and biodegradable hollow mesoporous organosilica (HMOS) nanoparticles show superior advantages for targeted CDDP delivery but suffer from premature CDDP leakage. Herein, the smart use of a bimetallic Zn2+/Cu2+ co-doped metal-organic framework (MOF) is made to block the pores of HMOS for preventing potential leakage of CDDP and remarkably increasing the loading capacity of HMOS. Once reaching the acidic tumor microenvironment (TME), the outer MOF can decompose quickly to release CDDP for chemotherapy against cancer. Besides, the concomitant release of dopant Cu2+ can deplete the intracellular glutathione (GSH) for increased toxicity of CDDP as well as catalyzing the decomposition of intratumoral H2O2 into highly toxic center dot OH for chemodynamic therapy (CDT). Moreover, the substantially reduced GSH can also protect the yielded center dot OH from scavenging and thus greatly improve the center dot OH-based CDT effect. In addition to providing a hybrid HMOS@MOF nanocarrier, this study is also expected to establish a new form of TME-unlocked nanoformula for highly efficient tumor-specific GSH-depletion-enhanced synergistic chemotherapy/chemodynamic therapy.

Automated summary

This study achieved targeted delivery of cisplatin using biocompatible and biodegradable hollow mesoporous organosilica (HMOS) nanoparticles by blocking the pores with a bimetallic Zn2+/Cu2+ co-doped metal-organic framework (MOF). The MOF decomposes in the acidic tumor microenvironment to release cisplatin for chemotherapy, while the released Cu2+ depletes intracellular glutathione (GSH) and catalyzes the decomposition of intratumoral H2O2 into highly toxic •OH for chemodynamic therapy. The reduced GSH also protects the •OH from scavenging, enhancing the chemodynamic therapy effect.