This article describes the development and characterization of a new drug delivery system called Liquid In Situ-Forming Tough (LIFT) hydrogels, which bridge the advantages of solid and liquid dosage forms. LIFT hydrogels are designed to form directly in the stomach through the sequential ingestion of a crosslinker solution (calcium chloride and dithiol crosslinkers) followed by a drug-containing polymer solution (alginate and four-arm poly(ethylene glycol)-maleimide). These hydrogels are mechanically robust, biocompatible, and can be safely cleared from the body within 24 hours. They deliver a total drug dose comparable to unencapsulated drugs in a controlled manner and protect encapsulated therapeutic enzymes and bacteria from gastric acid-mediated deactivation. The study demonstrates that LIFT hydrogels form robustly in the stomachs of live rats and pigs, exhibit enhanced mechanical properties compared to alginate hydrogels, and can modulate small molecule release, protect therapeutic enzyme activity, and support bacterial viability. Overall, LIFT hydrogels offer a promising solution for patients with difficulty swallowing, expanding access to advanced therapeutics.This article describes the development and characterization of a new drug delivery system called Liquid In Situ-Forming Tough (LIFT) hydrogels, which bridge the advantages of solid and liquid dosage forms. LIFT hydrogels are designed to form directly in the stomach through the sequential ingestion of a crosslinker solution (calcium chloride and dithiol crosslinkers) followed by a drug-containing polymer solution (alginate and four-arm poly(ethylene glycol)-maleimide). These hydrogels are mechanically robust, biocompatible, and can be safely cleared from the body within 24 hours. They deliver a total drug dose comparable to unencapsulated drugs in a controlled manner and protect encapsulated therapeutic enzymes and bacteria from gastric acid-mediated deactivation. The study demonstrates that LIFT hydrogels form robustly in the stomachs of live rats and pigs, exhibit enhanced mechanical properties compared to alginate hydrogels, and can modulate small molecule release, protect therapeutic enzyme activity, and support bacterial viability. Overall, LIFT hydrogels offer a promising solution for patients with difficulty swallowing, expanding access to advanced therapeutics.