Many biologics have a short plasma half-life, and their conjugation to polyethylene glycol (PEG) is commonly used to solve this problem. Unfortunately, PEG is immunogenic and forms vacuoles, and improvement in PEGylated drugs' half-life is at an asymptote. Here, we developed a PEG-like, non-immunogenic, and injectable conjugate technology for sustained delivery of biologics. An optimal poly[oligo(ethylene glycol) methyl ether methacrylate] (POEGMA) depot of exendin, a peptide drug used in the clinic in treating type 2 diabetes, outperformed PEG, non-depot-forming POEGMA, and a clinical sustained-release exendin-4 formulation in efficacy and pharmacokinetics. Notably, POEGMA was non-immunoreactive, while PEG induced a persistent anti-PEG immune response, leading to its subsequent doses' early clearance and loss of efficacy. POEGMA did not induce vacuolization. Solving these problems of PEG and improving upon its half-life benefits by creating injectable POEGMA conjugates that form a drug depot under the skin and provide sustained efficacy breathe new life into an established and valuable drug delivery technology that is facing an impasse.

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