Here is a list of ways bioactivity is achieved in 6 cases via 7 mechanisms:

Cyclization + N-methylation — lipophilicity, protease resistance (cyclosporine)

D-amino acid substitution — protease evasion (desmopressin)

Permeation enhancers — transient tight-junction opening or membrane fluidization (semaglutide/SNAC, insulin formulations)

Extreme potency — tolerating <1% bioavailability (desmopressin)

Minimizing size to di/tripeptides — exploiting PepT1 active transport (collagen hydrolysates)

Prodrug masking — protecting reactive groups, intracellular unmasking (S-acetyl-glutathione)

Local buffering — pH microenvironment control (semaglutide)

One I take, PEP19, apparently is unique in being naturally bioactive. Evidence is early stage, but I get noticably better sleep with it (by some non-drowsiness mechanism), taking 6mg, 3x the recommended dosage for sleep, but the higher dose may 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.

Despite a plethora of peptides, successes are not common.