Mussel-Inspired Membrane Encapsulation Strategy for Developing Long-Acting Glucose-Responsive Injectable Insulin Crystals

Abstract

Inspired by the catechol-lysine synergy and oxidative cross-linking mechanisms in mussel adhesion, we have synthesized poly-l-lysine (PLL) modified with 3,4-dihydroxyphenylacetic acid (DOPAC) to encapsulate insulin crystals. Upon oxidation, a dense, stable, and uniform membrane with nanochannels is in situ formed on the surface of insulin crystals, achieving high drug encapsulation efficiency, loading content, and sustained release performance. After further functionalization with 4-carboxy-3-fluorophenylboronic acid (FPBA), the membrane can mediate insulin release in a glucose-responsive manner. Notably, beyond the conventional charge switch induced by the binding between glucose and FPBA, molecular dynamics simulation identifies that glucose binding weakens noncovalent interactions among polymer chains and reduces membrane compactness, thereby accelerating insulin release. A single injection of encapsulated insulin crystals maintains normoglycemia for up to 218 and 190 h, respectively, in type 1 diabetic mouse and minipig models. This formulation also exhibits in vivo glucose-responsive insulin release, low risk of hypoglycemia, biodegradability, and high biocompatibility. This study presents a bioinspired membrane-enclosed strategy for developing long-acting and injectable formulations for hydrophilic drugs.