Innovative peptide formulations for cardiovascular diseases using supercritical CO₂: A comprehensive review and potential applications

Cardiovascular diseases (CVDs) remain the leading cause of morbidity and mortality worldwide, creating an urgent need for novel therapeutic strategies and advanced manufacturing processes that are scalable and cost-effective. Peptide-based drugs offer high specificity, potency, and favorable safety, yet their translation is limited by poor stability, enzymatic degradation, and low bioavailability. Supercritical carbon dioxide (scCO₂) has emerged as a promising technology to address these challenges through versatile formulation options, including polymeric and lipid nanoparticles and liposomes. This review discusses promising cardiovascular peptide therapeutics, summarizes key formulation strategies, the limitations of current manufacturing techniques and the main characteristics of various scCO₂-based processes for peptide formulation development. The advantages of scCO₂ over conventional methods, including enhanced product quality, the ability to process thermosensitive compounds at low temperatures, and minimal/no use of organic solvents, are discussed alongside current challenges, scale-up considerations, and knowledge gaps. Finally, future directions and translational opportunities are considered, emphasizing the potential of scCO₂ as an enabling platform for next-generation peptide therapeutics in cardiovascular health.