Breaking Biological Barriers: Engineering Nanocarriers for Efficient Drug and Gene Delivery through Nano-Bio Interfaces and Biophysical Design

Abstract

A persistent challenge in nanomedicine is achieving functional delivery of therapeutic molecules across physiological barriers. Organs impose distinct transport constraints, including the blood–brain barrier, renal filtration, hepatic sequestration, and pulmonary clearance. Although substantial effort has focused on engineering particle structure and surface chemistry, therapeutic performance also depends on dynamic interactions at the nano–bio interface. This structured critical narrative review compares how nanoparticle design variables interact with organ-specific transport mechanisms, prioritizing mechanistic primary studies and direct clinical or regulatory evidence while preserving study-specific experimental conditions. Most review papers focus on a single disease or summarize the progress of a specific nanoparticle type. In contrast, this review addresses the heterogeneity of biological filters by proposing a barrier-specific engineering framework. We evaluate diverse high-barrier environments with distinct restrictive mechanisms and describe the strategies used to overcome them in nanoparticle design. Specifically, we focus on how matching physicochemical properties to these environments can bypass physiological constraints. Using a comparative analysis methodology, we evaluate how design parameters, including size, morphology, and surface functionalization, interact with the mechanisms of major organ systems. Applying this framework across biological barriers distinguishes study-specific relationships from potentially transferable design principles. Its clinical and translational relevance is illustrated by engineered blood-brain barrier shuttles for Hunter syndrome and Alzheimer disease, lipid nanoparticle platforms for mRNA vaccination, and inhaled liposomal therapies.