Strategic shift to oral delivery: Oral peptide nano-formulations address the critical need for non-invasive, chronic administration. Enhancer-centric design: The review advocates for using permeation enhancers with established regulatory precedence. Focus on reproducibility: Viability in oncology is defined by controlled pharmacokinetic variability and reproducible exposure. Minimalist architecture: Lipid-based nano-platforms that facilitate peptide–enhancer co-localization over complex, novel structures. Translational priorities: Development pathways must prioritize CMC robustness and scale-up feasibility, and for successful commercialization.
ABSTRACT
Breast cancer is increasingly managed as a long-term condition, intensifying the need for therapies that are effective, tolerable, and suitable for chronic administration. Peptide-based therapeutics offer high molecular specificity and favorable safety profiles; however, their clinical utility remains largely limited by reliance on parenteral delivery. Oral administration is strategically attractive for improving patient adherence, quality of life, and healthcare efficiency, yet peptide drugs face formidable gastrointestinal barriers, including enzymatic degradation, restricted epithelial permeability, and substantial pharmacokinetic variability. These challenges may be further exacerbated by treatment-related gastrointestinal dysfunction in oncology populations. This review critically evaluates oral peptide nano-formulations that incorporate molecular permeation enhancers with established regulatory precedence as a pragmatic approach to achieving clinically meaningful oral absorption in breast cancer. Rather than emphasizing formulation novelty, the article adopts a translational, industry-oriented perspective that prioritizes regulatory alignment, chronic-use safety, manufacturability, and CMC robustness. Mechanistic and translational aspects of key enhancer classes—including medium-chain fatty acids, bile-derived agents, and surfactant-based enhancers—are examined, with particular attention to epithelial reversibility, dose–response nonlinearity, gastrointestinal tolerability, and exposure consistency. Evidence supports an enhancer-centric paradigm which primarily serves to protect peptides and co-localize peptide–enhancer exposure at the intestinal absorption site.
