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

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.

Introduction

Recent advancements in biotechnology and molecular biology have led to the development of new biotherapeutics based on peptides and proteins. These peptide and protein (PP) therapeutics offer unique biological functions and are generally well-tolerated upon administration. The global PP therapeutics market has been on a robust growth trajectory. It was valued at $42.8 billion in 2023 and is expected to grow at a compound annual growth rate of 7.9% between 2024 and 2032, potentially surpassing $80 billion by 2033 [1]. This growth aligns with the increasing share of biologics in new drug approvals, which has consistently ranged between 30% and 40% in recent years. Thus, almost half of the new molecule entities currently being developed by pharmaceutical companies are PP therapeutics [2].

These drugs possess significant therapeutic potential owing to their high specificity, potency, and ability to target diverse biological pathways [3]. Recently, they have been used to treat various conditions such as diabetes, cancer, cardiovascular diseases, inflammatory disorders, and hormonal imbalances [4]. Several clinical trials of PP therapeutics have been initiated, and many products have been approved—including salmon calcitonin, octreotide, and glucagon-like peptide 1 (GLP-1) agonists (e.g., semaglutide)—to improve the oral delivery of peptide therapeutics [5,6,7]. The growth of PP therapeutics has been driven by the rising prevalence of chronic diseases, advances in biotechnology, and their unique target specificity. Owing to their high specificity in binding capacity with their targets in vivo, PPs offer higher potency and specificity than small-molecule drugs, often resulting in more pronounced effects with fewer adverse side effects [8].

Most of these PPs are currently limited to intravenous injections, owing to their inherent short in vivo biological half-lives due to their rapid clearance in the liver and other body tissues by proteolytic enzymes [9]. However, parenteral administration burdens patients because of its invasive nature, leading to risks of immunogenic effects and poor compliance [10]. Notably, the requirement of administration by injection is associated with low patient compliance, especially in chronic treatments. Therefore, finding an alternative and non-invasive route to administer PP therapeutics has become a focal point of biopharmaceutical research.

Oral administration is the preferred and most convenient route of drug administration, as it is associated with higher patient compliance, lower risk of immunogenicity, and lower production costs compared to injectables. Despite the therapeutic potential of PPs, oral administration is often limited by inherent biopharmaceutical limitations such as limited solubility in the intestinal environment, short half-life, high molecular weight, hydrophilicity, susceptibility to enzymatic degradation, low permeability across the intestinal epithelium, and low stability in the gastrointestinal (GI) tract—all of which ultimately lead to poor oral bioavailability [11,12,13]. These key barriers demand extensive research on developing innovative strategies to improve the oral stability, absorption, and bioavailability of PP therapeutics.

Recent advancements have drawn attention to developing various oral PP delivery systems. These systems are usually integrated with functional excipients, including pH modulators, enzyme inhibitors, absorption enhancers, cell-penetrating peptides, hydrophobic ion pairing (HIP), and mucoadhesive polymers. Various drug delivery systems (DDSs)—including microemulsions, self-emulsifying DDSs (SEDDS), liposomes, solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs), lipid-polymeric hybrid systems (LPHs), hydrogels, and other smart-ingestible medical device have shown promising results in terms of overcoming the barriers to PP delivery [14,15,16]. Such strategies extend residence time, target specificity, and controlled release kinetics, substantially improving the oral bioavailability of PPs.

Despite this significant progress, specific challenges persist in designing reproducible oral delivery systems. The intricate interactions of factors such as drug release kinetics, particle size, carrier stability, and the impact of food intake necessitate continuous optimization and improvement. Numerous reviews on oral PPs emphasize theoretical advancements or preclinical findings, often overlooking clinical translation. This review outlines the challenges to delivering PPs orally and highlights various innovative research strategies used to address them, with a primary focus on clinical applications. We also assess emerging smart-ingestible device technologies aiding oral PP delivery, a rarely explored topic, and evaluate their effectiveness in overcoming physiological barriers. Furthermore, we examine ongoing clinical trials, new product approvals, and regulatory issues, providing a comprehensive overview of the evolving oral PP therapeutics landscape. By focusing on translational impact rather than just experimental progress, this review offers an organized perspective that transcends traditional discussions.

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Baral, K.C.; Choi, K.Y. Barriers and Strategies for Oral Peptide and Protein Therapeutics Delivery: Update on Clinical Advances. Pharmaceutics 2025, 17, 397. https://doi.org/10.3390/pharmaceutics17040397