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BackgroundBioactive peptides derived from natural sources (marine organisms, plants, microbes, and fermented foods) exhibit potent antimicrobial, antihypertensive, antioxidant, and anticancer activities. However, their clinical translation is severely hindered by poor oral bioavailability, rapid proteolytic degradation, suboptimal pharmacokinetic profiles, and inconsistencies in sourcing and standardization.ObjectiveThis review critically examines experimental pharmacology strategies to overcome these translational barriers, including in vitro permeability models, in vivo pharmacokinetic profiling, chemical modifications (cyclization, D-amino acid substitution, N-methylation, PEGylation), advanced delivery systems (liposomes, polymeric nanoparticles, pH-responsive hydrogels), and emerging AI/ML-guided approaches.Key findingsMost unmodified natural peptides display apparent permeability coefficients below 5×10−7 cm/s and plasma half-lives shorter than 15 min. Chemical modifications and nanocarrier systems demonstrably improve absorption and extend half-life, with reported increases in oral bioavailability of 3- to 10-fold in preclinical models. Success stories (ziconotide, lactotripeptides IPP/VPP) versus stalled candidates highlight the decisive role of integrated experimental pharmacology data. Critical gaps remain, including limited human pharmacokinetic evidence, scalability of nanocarriers under GMP conditions, and harmonized regulatory pathways for natural-origin peptides.ConclusionRigorous experimental pharmacology, rather than bioactivity alone, is the key to bridging the bench-to-bedside gap for natural bioactive peptides. A standardized translational workflow from discovery to IND filing is proposed to accelerate clinical application of these promising molecules.