Barriers and Strategies for Oral Peptide and Protein Therapeutics Delivery: Update on Clinical Advances

Abstract

Peptide and protein (PP) therapeutics are highly specific and potent biomolecules that treat chronic and complex diseases. However, their oral delivery is significantly hindered by enzymatic degradation, instability, and poor permeability through the gastrointestinal (GI) epithelium, resulting in low bioavailability. Various strategies have emerged as transformative solutions to address existing challenges, offering enhanced protection, stabilization, and absorption of PPs. These strategies primarily focus on two major challenges: protecting the PP against harsh conditions and enhancing permeation across the intestinal membrane. Innovative approaches such as pH modulation and incorporation of enzyme inhibitors are usually used to mitigate proteolytic degradation of PP during transit across the GI tract. In a similar vein, absorption enhancers and prodrug strategies facilitate epithelial transport, while targeted delivery systems focus on specific areas of the GI tract to enhance absorption. Likewise, mucus-penetrating and mucoadhesive strategies have enhanced retention and interaction with epithelial cells, effectively overcoming barriers like the mucus layer and tight epithelial junctions. Furthermore, structural modifications such as lipidation, peptide cyclization, and polyethylene glycosylation are promising alternatives to render stability, prolong circulation time, and membrane permeability. In particular, functional biomaterials, active targeting, and lymphatic transport strategies have provided new platforms for oral PP delivery. Advancing in materials science, nanotechnology, and the disruption of medical devices holds new frontiers to overcome barriers. Despite substantial advancements, the limited success in clinical translation underscores the urgency of innovative strategies. This review presents oral PPs as a promising platform, highlighting the key barriers and strategies to transform their therapeutic landscapes.

Keywords: bioavailability enhancement; enzymatic degradation; oral drug delivery; protein therapeutics.

Figure 1

Barriers to oral PP delivery. (A) Physicochemical barrier. The harsh conditions of the GI tract, including pH, enzymatic degradation (such as pepsin, lipase, proteases, and bile salts), and microbial activity, compromise the stability and absorption of oral PPs. (B) Cellular barrier. The intestinal epithelium contain specialized cells such as microfold cells, goblet cells, paneth cells, and enteroendocrine cells as well as tight junctions, which restrict paracellular transport of PPs into systemic circulation. (C) Mucus barrier. The mucus layer serves as both a steric and interactive barrier, restricting PP diffusion and leading to entrapment, which reduces its overall bioavailability. The figure was created using Biorender.com.

Figure 2

Various strategies for efficient oral delivery of PPs (1) Stabilization of PPs in the harsh gastrointestinal environment against enzymes, salts, and microbiota. (2) Mucoadhesive system. (3) Enhancement of mucodiffusion through the mucus-penetrating agents. (4) Inhibition of drug efflux mechanism. (5) Active targeting. (5.1) Functionalized ligands that interact with specific cell populations (enterocytes or goblet cells). (5.2) Delivery system act as targeting ligands by themselves. (6) Enhancing lymphatic transport system. (6.1) Chylomicrons, including lipids and hydrophobic cargo molecules from the internalized nanocarriers, are generated within enterocytes and absorbed by the lymphatic system. (6.2) Lymphatic uptake can also be achieved via M cells. The figure was created using Biorender.com.

Figure 3

Hydrophobic ion complex (HIP) of peptide molecules with counterions via ionic interactions. The figure was created using Biorender.com.

Figure 4

Delivery of oral semaglutide administration based on SNAC technology. SNAC enhances the oral delivery of semaglutide by raising the local gastric pH, protecting it from proteolytic degradation, and promoting monomerization. Additionally, it fluidizes lipid membranes, increasing their permeability and enabling efficient transcellular absorption of semaglutide into the systemic circulation. The figure was created using Biorender.com.

Figure 5

(A) Design of SOMA. The SOMA is designed to localize to the stomach lining, align its injection mechanism with the tissue wall, and deliver a drug payload through the mucosa. After the drug dissolves, the remainder of the device is expelled from the body. Self-orientation towards the desired upright position is provided by a high-curvature upper shell and a shifting of the center of mass. Once in its preferred orientation, the SOMA swiftly orients and stays stable in the stomach environment. Adapted from [152] with permission © 2019 American Association for the Advancement of Science. (B) Scheme of LUMI actuation, overhead (top), and side-view (bottom) images of an unfolded LUMI. Lumi devices were encapsulated in waterproof enteric capsules for ingestion. Upon reaching the small intestine, they actuated and unfolded, delivering drug-loaded microneedles in to the tissue wall. The microneedles patches and arms dissolved within a few hours, while the non-degradable components passed though the GI tract, and were eventually excreted. Adapted from [153] with permission © 2019 Springer Nature. (C) CAD design and device timeline of L-SOMA. Adapted from [155] with permission © 2021 Springer Nature. (D) Schematic illustrations of composition, release, drug delivery, and operational principle of the oral magneto-responsive microneedle robots (MMR). Adapted from [156] with permission © 2021 Wiley-VCH GmbH. (E) Micrograph showing a size 9 gelatin capsule containing coated micro-containers for delivering oral insulin [157].

Figure 6

Delivery of oral PP loaded in mucoadhesive patches.