Peptide- and protein-based therapeutics offer realized and potential benefits to health, due to their potent bioactivity, high specificity, and favorable safety characteristics. However, their widespread clinical application is constrained by inherent limitations, including rapid enzymatic degradation, poor membrane permeability, and a reliance on parenteral administration, which reduces patient adherence. To overcome these challenges, extensive research has explored non-invasive delivery strategies, including topical, transdermal, and oral formulations. Despite promising advances in these delivery strategies, they are yet to overcome substantial biological and physicochemical barriers in peptide and protein therapeutics, such as enzymatic degradation in the gastrointestinal tract, limited epithelial transport, and inherently low systemic bioavailability. This review provides a comprehensive and up-to-date analysis of the structural and physiological barriers influencing peptide and protein bioavailability and therapeutic efficacy. It critically examines key challenges associated with various administration routes, including topical, transdermal, oral (including delivery targeting the brain), and others. Furthermore, it explores innovative strategies to enhance peptide and protein stability and bioavailability, including chemical modifications, enzyme inhibitors, penetration enhancers, physical delivery technologies, and advanced nanoparticulate formulations. Additionally, emerging trends in formulation optimization, regulatory considerations, and translational pathways for clinical implementation are discussed. By addressing these critical challenges and highlighting recent advances, this review serves as a roadmap for the development of next-generation peptide and protein therapeutics with improved stability and efficacy, and enhanced patient adherence, which is needed to fully realize the true potential of this class of therapeutics.

Peptides and proteins  /  Skin barriers  /  Gastrointestinal barriers  /  Blood-brain barriers  /  Penetration enhancers  /  Enzymatic inhibitors  /  Chemical modification  /  Nanoparticulate drug delivery systems