Mechanochemical‐Induced Swelling–Activation of a Gastric‐Deployable 4D‐Printed Polypill Inspired by Natural Hygromorphic Actuators

Gastroretentive drug delivery systems can improve adherence in patients with chronic diseases (CDs), but current options lack dose flexibility and involve complex fabrication methods. Inspired by the hygroscopic deformation observed in multilayered pine cone scales, wherein hydration of the outer active layer induces cone closure, a one‐step fabrication method of a personalized 4D‐printed water‐actuated four‐arm polypill is demonstrated in this study. The bilayer‐arm polypill self‐deploys upon ingestion to prolong gastric retention and sustain drug release. By inversing the orientation of the swellable active layer at the polypill arms compared to pine cone scales, a differential swelling strain develops generating bending force that enables polypill deployment to constrain passage through the pylorus. Finite‐element analysis is used to model spatial changes in polymer phase swelling to ensure adequate deployment within the timeframe of gastric emptying. In a stomach model, the polypill expanded to 30 mm over 2 h, exceeding the diameter of the stomach model's distal end. In an in vitro release screening, biocompatible polymer composites capable of providing up to 6 days of release for a three‐drug combination for tuberculosis–HIV coinfected patients are identified. The bioinspired 4D‐printed polypill can serve as drug delivery platform for a range of CDs.