Mechanisms of Active Targeting and Cellular Internalization of Surface-Engineered Lipid Nanocarriers for Site-Specific Oncological Interventions

Review Article

Abstract

Chemotherapeutic efficacy is frequently compromised by non-specific systemic distribution, multidrug resistance, and suboptimal intracellular accumulation within malignant tissues. Lipid-based nanocarriers, particularly liposomes and solid lipid nanoparticles, represent a dominant class of drug delivery systems due to their biocompatibility and capacity to encapsulate diverse hydrophobic and hydrophilic payloads. While first-generation nanocarriers relied on the Enhanced Permeability and Retention (EPR) effect for passive accumulation, clinical translation has highlighted significant heterogeneity in tumor vasculature permeability, necessitating a shift toward active targeting strategies. Functionalization of the nanocarrier surface with specific ligands including monoclonal antibodies, peptides, aptamers, and small molecules like folate facilitates direct interaction with overexpressed receptors on the tumor cell surface. This molecular recognition triggers receptor-mediated endocytosis, bypassing conventional diffusion barriers and enhancing the cytosolic bioavailability of the therapeutic agent. Critical physicochemical parameters, such as ligand density, tether length, and nanocarrier elasticity, fundamentally dictate the binding avidity and subsequent intracellular trafficking pathways. This review discusses about the transition of lipid nanocarriers from passive retention to active molecular targeting and the influence of surface architecture on cellular uptake kinetics. The optimization of these surface-engineered systems offers a pathway to maximize the therapeutic index while minimizing off-target cytotoxicity in precision oncology