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Needle-based injections currently enable the administration of a wide range of biomacromolecule therapies across the body, including the gastrointestinal tract 1-3 , through recent developments in ingestible robotic devices 4-7 . However, needles generally require training, sharps management and disposal, and pose challenges for autonomous ingestible systems. Here, inspired by the jetting systems of cephalopods, we have developed and evaluated microjet delivery systems that can deliver jets in axial and radial directions into tissue, making them suitable for tubular and globular segments of the gastrointestinal tract. Furthermore, they are implemented in both tethered and ingestible formats, facilitating endoscopic applications or patient self-dosing. Our study identified suitable pressure and nozzle dimensions for different segments of the gastrointestinal tract and applied microjets in a variety of devices that support delivery across the various anatomic segments of the gastrointestinal tract. We characterized the ability of these systems to administer macromolecules, including insulin, a glucagon-like peptide-1 (GLP1) analogue and a small interfering RNA (siRNA) in large animal models, achieving exposure levels similar to those achieved with subcutaneous delivery. This research provides key insights into jetting design parameters for gastrointestinal administration, substantially broadening the possibilities for future endoscopic and ingestible drug delivery devices., Competing Interests: Competing interests: D. Sticker, A.G., T.D., B.M., J.P.H.J., D. Schultz, E.M.D.A., M. Poulsen, C.A., H.D.P., N.E.E., C.C., A.H.U., M. Pereverzina, R.K.K., C.M.D., S.B.G., I.P., A.B., A.A., M.R.F., P.H., U.L.R., J.J.W. and S.T.B. are employees and shareholders of Novo Nordisk. G.T. has received consulting fees and grant funding from Novo Nordisk. B.M., J.P.H.J. and M.R.F. are inventors of the following patent: ‘Jensen, B. et al. Medical Device with Actuation Mechanism. WO2020157324 (6 August 2020)’. G.A., D. Sticker, A.G., Y.L., D.G., B.M., J.W., J.P.H.J., T.S.L., C.C., S.Y., A.B., N.R., J.J.W. and G.T. are inventors of the following patent: ‘Arrick, G. et al. Drug Delivery Device. WO2022034041 (17 February 2022)’. G.A., D. Sticker, A.G., D.G., J.W., J.P.H.J., M. Poulsen, C.C., J.J.W. and G.T. are inventors of the following patent: ‘Traverso, G. et al. Ingestible Drug Delivery Device. WO2022035750 (17 February 2022)’. The other authors declare no competing interests., (© 2024. The Author(s).)