Oral delivery of biologics: from barrier-limited formulation to active convective transport.

Biologic therapeutics have transformed the treatment of chronic and life-threatening diseases, yet their clinical use depends almost entirely on parenteral administration. Oral delivery is the preferred route for patients, but it remains challenging for proteins, peptides, and other macromolecules. The gastrointestinal tract blocks their absorption through size exclusion at tight junctions, the hydrophobic lipid bilayer of enterocytes, restricted receptor-mediated uptake, and enzymatic degradation in the lumen and at the brush border. Decades of work on formulation strategies and chemical permeation enhancers have yielded only modest, inconsistent gains. For most biologics, absolute oral bioavailability stays below 1% under physiological conditions. These limitations have prompted a shift from passive transport strategies to active, force-based delivery. Over the past decade, ingestible device platforms have advanced along a clear developmental sequence: early microneedle systems established feasibility in animals, mucus-clearing robotic capsules and liquid-injection auto-injectors extended the approach to liquid biologics in large-animal models, and self-pressurized convective capsules introduced an excipient-driven mechanism requiring no moving parts. This progression culminated in the first Phase 1 human study, which showed that device-based oral delivery of a full-length IgG antibody can match the bioavailability of subcutaneous injection. That result confirms that mechanical bypass of gastrointestinal barriers is achievable in humans and sets a reference point for the field. This review traces the development of active oral biologic delivery systems from early preclinical work to clinical supply, with a focus on convective, force-enabled approaches using self-pressurized capsule technologies. We describe the gastrointestinal barriers that passive strategies cannot overcome, compare device-based platforms by mechanism and evidence, and examine the physical and engineering principles underlying self-pressurized capsule design. We also propose criteria for selecting candidate drugs and address safety, regulatory classification, and manufacturing requirements. The analysis places convective oral delivery within the broader class of force-based platforms and identifies what each system requires to advance.