AbstractEnfuvirtide (T‐20) is a synthetic peptide fusion inhibitor for the human immunodeficiency virus (HIV), which causes acquired immunodeficiency syndrome (AIDS). However, the peptide nature limits a wider application of T‐20 with subcutaneous injection (Fuzeon) the only available formulation. In this groundbreaking study, it is sought to overcome this limitation by employing poly lactic‐co‐glycolic acid (PLGA) and alginate to create novel oral delivery systems for T‐20. Remarkably, this investigation marks the first instance of assessing the efficacy of oral delivery systems in mice. Notably, both the PLGA and alginate formulations exhibit the capability to sustain T‐20 release, maintaining detectable levels in the bloodstream of mice for over 24 h after a single dose. By venturing into the realm of oral T‐20 delivery, this study opens avenues for the prospective development of oral formulations of T‐20, potentially leading to their evaluation in clinical trials.