Peptide-assembled siRNA nanomicelles confine MnOx-loaded silicages for synergistic chemical and gene-regulated cancer therapy

Chemodynamic therapy (CDT) is a promising therapeutic approach for in situ cancer treatment, but it is still hindered by inefficient single-modality treatment and the weak targeted delivery of reagents into mitochondria (the main site of intracellular ROS production). Herein, to obtain a multimodal strategy, peptide-assembled siRNA nanomicelles were prepared to confine ultrasmall MnOx in small silica cages (silicages), which is convenient for synergistic chemical and gene-regulated cancer therapy. Given the free energy and versatility of small silicages, as well as the excellent Fenton-like activity of ultrasmall MnOx, MnOx-inside-loaded silicages (10 nm) were prepared for CDT delivery to mitochondria. Subsequently, to obtain a synergistic CDT and gene silencing treatment, the peptide-mediated assembly of siRNA and MnOx-loaded silicages were employed to obtain silicage@MnOx-siRNA nanomicelles (SMS NMs). After multiple modifications, sequential cancer cell-targeted delivery, GSH-controlled reagent release of siRNA and mitochondria-targeted delivery of MnOx-loaded silicages were successfully achieved. Finally, by both in vitro and in vivo experiments, SMS NMs were confirmed to be effective for synergistic chemical and gene-regulated cancer therapy. Our findings expand the applications of silicages and initiate the development of multimodal CDT. Given the versatility of silica surface chemistry and its ability to distinguish inside from outside, small silicages (10 nm) are prepared to efficiently load ultrasmall MnOx with better biocompatibility and stabilities. The MnOx-loaded silicages are uniformly confined in peptide-assembled siRNA nanomicelles for multimodal therapy with spatial-temporal consistency. By multiple modifications, tumor-targeted delivery, as well as GSH-controlled reagent release of both MnOx-loaded silicages and siRNA were successfully employed, obtaining synergistic mitochondria-targeted chemodynamic therapy and gene-regulated cancer [Display omitted]