Polymer–Covalent Organic Frameworks Composites for Glucose and pH Dual‐Responsive Insulin Delivery in Mice

Abstract Glucose and pH dual‐responsive insulin delivery carriers that have been validated in animal models, remain elusive and much desired. Herein, a new class of covalent organic frameworks (COFs)‐based insulin delivery nanocarriers is developed by encapsulating insulin (Ins) and glucose oxidase (GOx) into COFs (COF‐1 and COF‐5) via both Brønsted and Lewis type (N:→B) complexations. Subsequently, polyethylene glycolated fluorescein isothiocyanate (FITC‐PEG) is incorporated into the COFs via the exchange reactions between the disulfide in insulin chains and the thiol in FITC‐PEG to afford a robust nano‐assembly (FITC‐PEG‐COF@Ins‐GOx). In vitro, the nanocarriers rely on the boroxine‐linked COFs’ response to pH and glucose dual‐stimulation and rendered sustainable insulin delivery. In vivo, the polymer–COFs composite displays excellent long‐acting anti‐diabetic effects on type 1 diabetic mice within 72 h without side effects after one injection. More intriguingly, the nanocomposites also show great promise for the efficient delivery of native proteins with high generality. To the authors’ knowledge, this represents the first study pertaining to a facile methodology to prepare COF‐based insulin‐delivery nanocarriers for in vitro and in vivo therapeutic applications.