Supramolecular Modular Approach toward Conveniently Constructing and Multifunctioning a pH/Redox Dual-Responsive Drug Delivery Nanoplatform for Improved Cancer Chemotherapy

Because heterogeneity affects many functional aspects of a tumor, a way to overcome it is to arm nanosized drug delivery systems (nanoDDS) with diverse functions required to shatter heterogeneity. However, it remains technically challenging to fabricate a nanocarrier possessing all required functions. Here, we propose a modular strategy for generating a supramolecular, multifunctional, and stimuli responsive nanoDDS through docking a parental core nanoDDS with various daughter function-prebuilt modules. Doxorubicin (DOX)-loaded mesoporous silica nanoparticles (MSNs) as the parental nanocore are wrapped by poly(beta-cyclodextrin) (PCD) as a gatekeeper through host-guest interactions between cyclodextrin units and pyridine groups of pyridine-disulfide bonds that confers pH/redox dual responsiveness, thus constructing stimuli-responsive nanoDDS (DOX@PRMSNs). Meanwhile, PCD's free cyclodextrin is tightly caged by adamantyl (Ad)-terminated daughter modules via host-guest interactions, achieving convenient multifunctionalization of this nanoDDS. DOX@PRMSNs rapidly released DOX in lysosomal pH/redox microenvironment, potently killing drug-resistant cancer cells. Further, three different types of Ad terminated daughter modules, including two targeting ligands (Ad-PEG-FA and Ad-PEG-LA), a cationic polymer (Ad-PEI), and a fluorescence agent (Ad-FITC), are utilized to functionalize PRMSNs via cyclodextrin-Ad self-assembly, endowing the nanoDDS with cell-targeting capability, gene codelivery property, and imaging function. Thus, this work develops a supramolecular modular self-assembly approach for constructing and multifunctionalizing stimuli-responsive "smart" nanoDDSs.