Boronic acid-modified cellulose nanocrystal-cored poly(propylene imine) dendrimers as biocompatible glucose-responsive nanocarriers for intelligent insulin delivery and sensing

Abstract

Precise regulation of blood glucose level is essential for the long-term and effective management of diabetes. In this context, glucose-responsive insulin delivery systems have emerged as an innovative strategy for smart and self-regulated insulin release. This study develops a nanocarrier based on nanocrystalline cellulose (CNC)-cored poly(propylene imine) (PPI) dendrimers (CPG) functionalized with 4-carboxyphenylboronic acid (CPB), denoted as CPG_x-CPB. Titration approach showed that dendrimer amine groups lowered the pK_a of CPB, improving its responsiveness at physiological pH. Insulin-loaded CPG₃-CPB and CPG₄-CPB systems achieved encapsulation efficiencies of 73.6% and 85.8%, and loading capacities of 17.8% and 21.7%, respectively. While the third-generation dendrimer provided greater internal space, the fourth generation offered more binding sites for insulin. Insulin release remained low (∼10%) under acidic conditions (simulated gastric fluid (SGF), pH = 1.2), but significantly increased under neutral conditions (simulated intestinal fluid (SIF), pH = 6.8) and elevated glucose levels, reaching up to 65% due to boronate-glucose complex formation. MTT assay showed ∼100% cell viability up to 200 μg/mL. Kinetic modeling showed that the Higuchi and Korsmeyer-Peppas models best fit the release profile. Furthermore, the system exhibited reversible glucose-responsive behavior, acting as a smart sensor through observable fluorescence and colorimetric changes.