This article introduces a novel drug delivery system called LIFT hydrogels, which can transition from a liquid to a solid form in the stomach. LIFT hydrogels are designed to overcome the challenges of traditional solid and liquid oral formulations. They combine ionic (calcium/alginate) and covalent (poly(ethylene glycol) (PEG)) polymer networks to enhance mechanical strength. The hydrogels are formed in the stomach through the sequential ingestion of a crosslinker solution containing calcium and a dithiol crosslinker, followed by a drug-containing polymer solution of alginate and four-arm PEG-maleimide. The hydrogels form robustly in the stomachs of live rats and pigs, are mechanically tough, biocompatible, and safely cleared after 24 hours. They deliver a total drug dose comparable to unencapsulated drug in a controlled manner and protect encapsulated therapeutic enzymes and bacteria from gastric acid-mediated deactivation. LIFT hydrogels offer advantages over traditional solid and liquid formulations, including enhanced gastric retention, protection against gastrointestinal proteases, mechanical toughness, and the ability to control drug release. They can also co-encapsulate sensitive therapeutics with excipients. The hydrogels are made from FDA-approved or GRAS materials, ensuring safety. They have been tested in large animals and shown to be safe, non-toxic, and non-obstructive. LIFT hydrogels can protect therapeutic enzymes and bacteria from the harsh gastric environment, as demonstrated by their ability to maintain lactase activity and bacterial viability in the presence of gastric fluid. They also show potential for delivering a variety of therapeutics, including small molecules, enzymes, and bacteria, with controlled release and protection from degradation. The study highlights the potential of LIFT hydrogels to expand access to advanced therapeutics for patients with difficulty swallowing. They can bridge the advantages of solid and liquid formulations, providing a safe and effective alternative for drug delivery. The hydrogels are capable of in situ gelation, which minimizes exposure of the dosage form to gastric fluid and allows for controlled release of therapeutics. They have the potential to be used in a wide range of applications, including gastric drug modulation, weight loss, and protection of encapsulated biologics. The study also discusses the broader implications of LIFT hydrogels for the future of oral drug delivery, emphasizing their potential to improve patient outcomes and treatment compliance.This article introduces a novel drug delivery system called LIFT hydrogels, which can transition from a liquid to a solid form in the stomach. LIFT hydrogels are designed to overcome the challenges of traditional solid and liquid oral formulations. They combine ionic (calcium/alginate) and covalent (poly(ethylene glycol) (PEG)) polymer networks to enhance mechanical strength. The hydrogels are formed in the stomach through the sequential ingestion of a crosslinker solution containing calcium and a dithiol crosslinker, followed by a drug-containing polymer solution of alginate and four-arm PEG-maleimide. The hydrogels form robustly in the stomachs of live rats and pigs, are mechanically tough, biocompatible, and safely cleared after 24 hours. They deliver a total drug dose comparable to unencapsulated drug in a controlled manner and protect encapsulated therapeutic enzymes and bacteria from gastric acid-mediated deactivation. LIFT hydrogels offer advantages over traditional solid and liquid formulations, including enhanced gastric retention, protection against gastrointestinal proteases, mechanical toughness, and the ability to control drug release. They can also co-encapsulate sensitive therapeutics with excipients. The hydrogels are made from FDA-approved or GRAS materials, ensuring safety. They have been tested in large animals and shown to be safe, non-toxic, and non-obstructive. LIFT hydrogels can protect therapeutic enzymes and bacteria from the harsh gastric environment, as demonstrated by their ability to maintain lactase activity and bacterial viability in the presence of gastric fluid. They also show potential for delivering a variety of therapeutics, including small molecules, enzymes, and bacteria, with controlled release and protection from degradation. The study highlights the potential of LIFT hydrogels to expand access to advanced therapeutics for patients with difficulty swallowing. They can bridge the advantages of solid and liquid formulations, providing a safe and effective alternative for drug delivery. The hydrogels are capable of in situ gelation, which minimizes exposure of the dosage form to gastric fluid and allows for controlled release of therapeutics. They have the potential to be used in a wide range of applications, including gastric drug modulation, weight loss, and protection of encapsulated biologics. The study also discusses the broader implications of LIFT hydrogels for the future of oral drug delivery, emphasizing their potential to improve patient outcomes and treatment compliance.