Natural amphiphilic co-polymers as sustainable nanocarriers for enhanced solubility of hydrophobic drugs

A major barrier to effective therapy is the limited water solubility of many Biopharmaceutics Classification System (BCS) Class II and IV medications, which results in poor bioavailability and inconsistent patient outcomes. Better solubilization and stability are provided by traditional synthetic nanocarriers such as PLGA, poloxamers, and PEG-PLA; however, these have disadvantages such as toxicity, cost, reliance on petrochemical resources, and regulatory barriers. Natural amphiphilic co-polymers (NACPs) are a sustainable and amiable alternative to proteins, polysaccharides, and phospholipids. Because of their innate amphiphilicity, which promotes self-assembly into micelles, vesicles, nanogels, and hydrogels, hydrophobic drugs can be effectively encapsulated and released under controlled conditions.This review focuses on the structural foundations of amphiphilicity in graft and block copolymers, naturally occurring self-assembling systems, and chemically modified derivatives that enhance solubility and drug-polymer interactions. In contrast to synthetic carriers, NACPs have other benefits such as mucoadhesion, enzymatic degradability, pH/enzyme responsiveness, and generally recognized as safe (GRAS) regulatory status, even though problems with scalability, reproducibility, and long-term stability still exist. Their versatility includes oral, parenteral, transdermal, pulmonary, nasal, and ocular drug delivery, with notable improvements in solubility, bioavailability, and therapeutic accuracy. Recent advancements include stimuli-responsive designs, hybrid natural-synthetic systems, and artificial intelligence (AI)-driven modeling for predicting drug-polymer compatibility. Collectively, NACPs present a sustainable strategy for next-generation nanomedicine that strikes a balance between therapeutic efficacy and environmental responsibility. By addressing solubility concerns with environmentally acceptable carriers, NACPs have a substantial translational potential to promote pharmaceutical innovation and green drug delivery systems.