A dual-response size-shrinkable drug delivery system capable of deep tumor penetration for the treatment of solid tumors.

The effective delivery of chemotherapeutic agents into solid tumors is a significant challenge in nanomedicine due to the "size paradox" between long circulation and deep tumor penetration. In this work, we developed a dual-responsive, size-shrinkable drug delivery system, DOX@US-DSMSN-Cluster, based on ultra-small, disulfide-bridged mesoporous silica nanoparticles (US-DSMSN). This system was constructed by loading doxorubicin hydrochloride (DOX) into ∼30 nm US-DSMSN, sealing their pores with β-cyclodextrin (β-CD) via click chemistry, and crosslinking the nanoparticles (NPs) with pH-sensitive benzoic imine-linked adamantane-di-terminated poly(ethylene glycol) (Ad-N=C-PEG-C=N-Ad) through host-guest interactions. This formed the DOX@US-DSMSN-Cluster with a size of ∼280 nm. This design enables prolonged blood circulation and enhanced tumor accumulation via the enhanced permeability and retention (EPR) effect. In an acidic tumor microenvironment (TME), the PEG shell detaches and releases smaller drug-loaded NPs that can penetrate deeply into tumors. Subsequently, the high intracellular concentration of glutathione (GSH) cleaves the disulfide bonds, triggering DOX release. In vitro and in vivo studies demonstrate that this system enhances tumor penetration and increases cellular uptake. It also exhibits potent antitumor efficacy with minimal systemic toxicity. This work presents a promising strategy to overcome delivery barriers in solid tumors through sequential size transformation and conditional drug release.