Nanochaperones tailored for insulin delivery to reduce immune clearance and enhance bioavailability of insulin

• Nanochaperones containing both PBA-modified hydrophobic domains and NTA-based coordination domains are prepared. • Nanochaperones could effectively and stably adsorb insulin. • Nanochaperones could stabilize the structure of insulin. • Nanochaperones could reduce immune clearance and prolong the half-life of insulin. • Insulin-adsorbed nanochaperones exhibited excellent hypoglycaemic effect. Insulin has been widely used in clinic for 40 years, but it still suffers from amyloid aggregation, proteolytic degradation and rapid clearance upon storage and administration. Inspired by zinc-coordinated insulin hexamer structure and natural molecular chaperones with protein transportation functions in vivo, tailor-made complex micelles with nitrilotriacetic acid (NTA)-based coordination moieties and PBA-modified hydrophobic domains on the surface were used as nanochaperones to mediate the delivery of insulin in this study. The NTA moieties could capture insulin by coordination with its histidine residual while the hydrophobic PBA domains could further bind insulin through interaction with its exposed hydrophobic sites. The nanochaperones efficiently load insulin through the synergy between the NTA moieties and the hydrophobic PBA domains, and masked the histidine residual and the hydrophobic segments of insulin, thus significantly reducing the immune clearance, improving the half-life of insulin (t 1/2 = 9.97 h). Moreover, the insulin-loaded nanochaperones (Ins/CMs-2) has good responsiveness to physiological hyperglycemia and insulin can be released in the natural form, thereby controlling blood glucose levels (BGLs) of diabetic mice in the normal range.