PEGylation is a promising strategy for modulating the physicochemical properties and improving the therapeutic efficacy of protein drugs. However, the application of multi-PEGylation frequently results in diminished protein activity. A single low molecular weight PEG (5 kDa) modified at the amino terminus of the B chain preserves the biological activity of insulin and moderately improves its pharmacokinetics. Nonetheless, this modification offers limited protein stabilization. Furthermore, overdoses still carry the risk of hypoglycemia, posing challenges for the clinical application of PEGylated insulin. Here, we constructed multifunctional nanochaperones featuring phenylboronic acid (PBA) modified hydrophobic microdomains and nitrilotriacetic acid (NTA)-based coordination domains (PN-nChaps) for PEGylated insulin delivery. This delivery strategy effectively overcomes the limitations associated with PEGylation by enhancing the stability and reducing the immunogenicity of PEGylated insulin, while enabling glucose-responsive controlled release. PEGylated insulin with nanochaperone carrier demonstrates a prolonged half-life (t1/2 = 18.66 h), facilitates on-demand release, and minimizes the risk of hypoglycemia. This approach provides a safe and effective strategy for long-term glycemic management in diabetic patients.

A novel strategy developed by combining PEGylated insulin with nanochaperone carriers to enhance insulin bioavailability for long-term glucose management.