Size and Charge Dual-Transformable Mesoporous Nanoassemblies for Enhanced Tumor Delivery and Penetration

A series of biological barriers in the nanoparticle-formulated drug delivery process inevitably result in the currently low delivery efficiency, limited tumor penetration and insufficient cellular internalization of drugs. The multiple biological barriers are intimately related to the physicochemical properties of nanoparticles, especially the contradictory demand on size and surface charge for long blood circulation (larger, negative), deep tumor penetration (smaller) as well as efficient cellular internalization (positive). Herein, we report the tumor microenvironment triggered size and charge dual-transformable nanoassemblies. The nanoassembly is realized by immobilizing positive up/downconverting luminescent nanoparticles (U/DCNPs) onto large mesoporous silica nanoparticles (MSNs) via acid-labile bonds to form the core@satellites structured MSN@U/DCNPs nanoassemblies, and subsequently capping of charge reversible polymers. At physiological pH, the integrated nanoassemblies with a larger size (~ 180 nm) and negative charge can effectively achieve a prolonged blood circulation and high tumor accumulation. While at acidic tumor microenvironment, the charge reversal of outer polymer and cleavage of linkers between MSNs and U/DCNPs can induce disintegration of the nanoassemblies into the isolated MSNs and smaller U/DCNPs, both with positively charged surface, which thereby potentiating the tumor penetration and cell uptake of dissociated nanoparticles. Combined with the independent near-infrared (NIR)-to-visible and NIR-to-NIR luminescence of U/DCNPs and high surface area of MSNs, the nanoassemblies can implement NIR bioimaging guided chemo- and photodynamic combined therapy with remarkable antitumor efficiency because of the high accumulation and deep tumor penetration induced by dual transformability of the nanoassemblies.