Layer by Layer Engineered Lipid-Based Nanocarriers for Therapeutic Delivery and Next-Generation Design

The biological fate of lipid-based nanocarriers (LBNs) is shaped at the interface. Whereas core architecture governs cargo loading, protection, and baseline release, surface architecture mediates the carrier’s initial interactions with proteins, cells, extracellular matrices, and tissue barriers, thereby influencing colloidal stability, immune recognition, targeting, biodistribution, barrier transport, and release initiation. Layer-by-layer (LbL) engineering provides a modular strategy for programming this interface through sequentially assembled coatings in which functional components are spatially separated yet mechanistically coordinated. By integrating polymers, biomolecules—including peptides and nucleic acids—and stimuli-responsive materials, LbL systems can decouple functions that are difficult to regulate independently within conventional single-layer or compositionally mixed surface architectures. This review examines recent advances in LbL-engineered LBNs (LbL-LBNs), focusing on how multilayer surface architecture reshapes physicochemical properties, cargo localization and release, biological identity, cellular interactions, and transport across physiological barriers. Particular attention is given to the multilayer interface as a dynamic biointerfacial bridge between a cargo-specific core architecture and the surrounding biological environment, including its capacity for stimuli-responsive switching in pathological microenvironments. The discussion further extends to biomimetic hybrid interfaces and establishes a framework for translating hierarchical surface architectures into reproducible, clinically tractable platforms for precision therapeutic delivery.