Polysaccharide-based nanogels have drawn considerable interest in pharmaceutics because of their superior biocompatibility and potential responsiveness to external stimuli, enabling specific drug release. During the fabrication of nanogels, however, covalent cross-linking often involves less friendly cross-linkers and traditionally employed noncovalent cross-linking often relies on weak interactions that may lead to premature payload release. Herein, we report host–guest chemistry-driven supramolecular chitosan nanogels (CNGs) that are responsive to either endogenous or exogenous stimuli, thus allowing selective drug release in specific cancer cells or disease sites. In an aqueous solution, two phenylalanine (Phe) units of Phe-grafted chitosan (CS-Phe) were encapsulated into one cavity of cucurbit[8]­uril (CB[8]), driving cross-linking of CS-Phe and formation of CNGs. Doxorubicin hydrochloride (DOX), a chemotherapeutic agent, was entrapped in the matrix of CNGs during the formation of nanogels to yield DOX–CNGs with an excellent drug loading efficiency. The morphology and size of CNGs were fully assessed by transmission electron microscopy and dynamic light scattering. The encapsulated DOX was selectively liberated in the presence of competitive guests of CB[8], such as endogenous spermine (SPM) that is overexpressed by certain types of cancer cells or exogenous amantadine (ADA) that may be added into cells or tissues that require targeted treatment, either of which may replace Phe from the cavity of CB[8] resulting in the breakdown of the nanogels and payload release. The CNGs were efficiently internalized by cells, and the DOX–CNGs exhibited specific, potent activity against cancerous cells such as A549 cell line that is well known for SPM overexpression. This study reports that the first stimuli (competitive guest)-responsive host–guest interactions initiated supramolecular CNGs with excellent biocompatibility and selective therapeutic efficacy against cancer cells. It may provide new insights into the design and fabrication of novel stimuli-responsive payload delivery systems.

The photosensitizer Chlorin e6 (Ce6) has been frequently employed for photodynamic therapy (PDT) of cancer; however, its nonspecific toxicity has limited its clinical applications. In this study, we prepared chitosan nanoparticles (CNPs), with a mean diameter of approximately 130 nm, by a nonsolvent-aided counterion complexation method in an aqueous solution, into which Ce6 could be physically entrapped during the preparation process. These CNPs and Ce6-loaded CNPs (CNPs-Ce6) were fully characterized by UV-vis, photoluminescence, and Fourier transform infrared spectroscopic analysis, as well as dynamic light scattering and transmission electron microscopy measurements. More importantly, the biocompatibility of the otherwise toxic Ce6 was significantly improved upon its loading into the CNPs, as demonstrated by both confocal laser scanning microscopy analysis and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Furthermore, the PDT efficiency of Ce6-loaded CNPs was dramatically enhanced, in comparison with that of the free Ce6, as shown by both MTT and flow cytometry assays. This discovery provides a novel strategy for improving the biocompatibility and therapeutic efficacy of PDT agents by using a natural, biocompatible polysaccharide carrier.

Surface functionalization of nanoparticles (NPs) is of pivotal importance in nanomedicine. However, current strategies often require covalent conjugation that involves laborious design and synthesis. Herein, cucurbit[7]uril (CB[7])-decorated poly(lactic acid) (PLA)/poly(lactic-co-glycolic acid) (PLGA) NPs are developed and exploited for the first time as a novel, biocompatible, and versatile drug delivery platform with a noncovalently tailorable surface. CB[7] on the surface of NPs, acting as a "Lego" base block, allowed facile, modular surface modification with a variety of functional moieties or tags that are linked with amantadine (a complementary "Lego" piece to the base block), including amantadine-conjugated folate, polyethylene glycol, and fluorescein isothiocyanate. In addition, surface CB[7] also provided an opportunity for encapsulation of a secondary drug, such as oxaliplatin, into the cavity of the base block CB[7], in addition to a primary drug (e.g., paclitaxel) loaded into PLA/PLGA NPs, for a possible synergistic chemotherapy. This proof of concept not only provides the first versatile PLA/PLGA nanomedicine platform with "Lego" surface for modular functionalization and improved drug delivery but also offers new insights into the design and development of novel nanomedicine with a modular surface.