Acidity/Reducibility Dual-Responsive Hollow Mesoporous Organosilica Nanoplatforms for Tumor-Specific Self-Assembly and Synergistic Therapy

Featured with a large surface area, uniform interpenetrating mesopores, diverse organic framework hybridization, and well-defined surface properties, the hollow mesoporous organosilica nanoparticle (HMON) represents a promising paradigm in drug delivery systems with excellent biocompatibility. However, effective tumor accumulation and precise cancer theranostics of the HMON still remain a challenge. In this study, an "ammonia-assisted hot water etching" method is applied for the successful construction of sub-50 nm thioether/phenylene dual-hybridized HMON with low hemolytic effect. Particularly, the surface modification with Mo(VI)-based polyoxometalate (POM) clusters drives the self-assembly of HMON in the mild acidic tumor microenvironment (TME) to achieve enhanced tumor retention and accumulation. More importantly, the reducibility-activated Mo(VI)-to-Mo(V) conversion within POM not only endows the POM-anchored HMON with outstanding TME-responsive photoacoustic (PA) imaging contrast and photothermal therapy (PTT) performance but also plays an indispensable role in controllably triggering the decomposition of the Mn2(CO)10 payload for CO release, which gives rise to remarkable synergistic PTT-enhanced CO gas therapy for complete tumor eradication. By harnessing the unique acidic and redox properties of TME, the judiciously designed smart POM-anchored HMON nanoplatform is expected to act as a "magic bomb" to selectively destroy cancer without damaging normal tissues. This nanoplatform holds significant potential in realizing TME-responsive self-assembly for enhanced tumor accumulation and precise tumor-specific synergistic therapy, which is very promising for clinical translation.