Molecular Engineering for On-Demand Therapeutic Delivery

M.J. Webber
University of Notre Dame,
United States

Keywords: drug delivery, diabetes, biomaterials, hydrogels


Managing blood glucose to better control diabetes entails rigorous therapy yet fails to fully restore natural glycemic control, leading to a myriad number of acute and chronic health complications that arise from blood glucose instability. Efforts toward more autonomous therapies struggle to match glucose sensing and therapeutic deployment of insulin with requisite temporal fidelity. Moreover, the delivery of glucagon to balance the effects of insulin in a bi-hormonal setting or reverse the onset of life-threatening low blood glucose events in emergency use remains a formidable challenge given the limited stability of this protein in formulation. We are designing formulations at the molecular scale to improve the stability and autonomy of insulin and glucagon and enhance both their short- and long-term efficacy in blood glucose control. Toward autonomous control of bioavailability and activity, active formulations relying on aryl boronate glucose sensors or actuated through pairing with glucose oxidase enzymes enable the tunable release and bioavailability of insulin and glucagon corresponding to their therapeutic need, as dictated by blood glucose level. Lead insulin formulation approaches enhance therapeutic stability, promote long duration of action, and achieve increased serum insulin levels in response to glucose challenge, even demonstrating week-long and active blood glucose control in diabetic swine. Likewise, complementary formulation approaches enable glucagon to be delivered with accelerated function upon onset of dangerously low blood glucose levels, reversing the most severe outcomes of insulin overdose. We envision that these approaches, centered on molecular engineering, formulation design, and responsive delivery of unmodified or minimally modified protein drugs, will yield therapeutic solutions that are safe, and more efficacious in managing the unique demands presented by dynamic blood glucose control.