Precision engineering of nanocarriers for transport across complex biological barriers

Biological barriers are essential for maintaining tissue homeostasis and protecting organs from harmful external agents; however, they also represent major obstacles to the efficient delivery of therapeutic agents. The blood-brain barrier, ocular barriers, mucosal barriers, and vascular endothelial barriers exhibit highly selective permeability that restricts the transport of both small-molecule drugs and biopharmaceuticals, thereby limiting tissue bioavailability, reducing therapeutic efficacy, and increasing the risk of systemic adverse effects. Advances in nanotechnology have enabled the development of precision-engineered nanocarriers capable of overcoming these barriers through the rational optimization of their physicochemical properties and interactions with biological interfaces. This review comprehensively explores recent advances in nanocarrier-based drug delivery systems designed to traverse complex biological barriers, with emphasis on transport mechanisms, engineering strategies, clinical translation, and future research directions. We relate barrier anatomy and physiology to nanocarrier trafficking and evaluate barrier-specific strategies, including receptor-mediated transcytosis and focused ultrasound-assisted reversible modulation for the blood-brain barrier, mucoadhesive and amphiphilic systems for ocular delivery, mucus penetration, and endothelial transport. We discussed how particle size, morphology, surface charge, ligand functionalization, and stimulus responsiveness affect barrier transport and therapeutic performance. Clinical translation is discussed through approved formulations and evidence from ongoing clinical trials. Future directions include artificial intelligence-assisted design, predictive modeling of nano-biointerface interactions, cell membrane-based biomimetic nanocarriers, and nanomedicine tailored to patient-specific barrier characteristics. These advances may enable safer, more effective therapies for diseases inadequately addressed by conventional drug delivery.