Here is a list of ways bioactivity is achieved:<p>Cyclization + N-methylation — lipophilicity, protease resistance (cyclosporine)<p>D-amino acid substitution — protease evasion (desmopressin)<p>Permeation enhancers — transient tight-junction opening or membrane fluidization (semaglutide/SNAC, insulin formulations)<p>Extreme potency — tolerating <1% bioavailability (desmopressin)<p>Minimizing size to di/tripeptides — exploiting PepT1 active transport (collagen hydrolysates)<p>Prodrug masking — protecting reactive groups, intracellular unmasking (S-acetyl-glutathione)<p>Local buffering — pH microenvironment control (semaglutide)<p>One I take, PEP19, apparently is unique in being naturally bioactive. Evidence is early stage, but I get better sleep with it, taking 6mg, 3x the recommended dosage. At the higher does it may also promote fat burning and fat browning at night (only 1 study). It only has 10 residues which apparently avoid having typical cleavage points, fragments may retain bioactivity, and it has extreme potency in very small doses so any absorption means a lot.<p>And the big one:<p>Mechanical injection — bypassing the absorption problem entirely (Rani pill)<p>But despite a plethora of peptides, successes are not common.