<p>Targeted anticancer therapies, including monoclonal antibodies, antibody–drug conjugates, siRNA, small-molecule inhibitors, and PROTACs, offer precise treatments but face severe pharmacokinetic and biological barriers, such as poor bioavailability, limited tumor penetration, and off-target toxicity. While first-generation lipid-based nanoparticles (LBNPs) successfully utilized the enhanced permeability and retention (EPR) effect, relying exclusively on passive targeting is insufficient due to tumor heterogeneity. Therefore, this review provides an integrative analysis focused on the rational design of LBNPs. We systematically explore how the distinct structural complexities and biological barriers of each therapeutic modality strictly dictate specific LBNP design rules. The optimization of various nanocarriers—including liposomes, solid-lipid nanoparticles, and nanostructured lipid carriers—is discussed through customized lipid compositions, surface functionalization for active targeting, and the incorporation of ionizable lipids to overcome intracellular barriers like endosomal entrapment. Furthermore, these structural designs are correlated with optimal administration routes, and the impact of formulation methods is evaluated by contrasting traditional emulsification with advanced continuous platforms like microfluidics and supercritical fluid technology. Finally, the clinical landscape and translational challenges of approved and experimental nanomedicines are assessed. We conclude that the transition from bench to bedside is currently hindered less by preclinical efficacy and more by manufacturing and regulatory bottlenecks. Overcoming chemistry, manufacturing, and controls (CMC) challenges, ensuring robust industrial scalability, and establishing harmonized regulatory frameworks are critical priorities for the future clinical success of targeted nanomedicines.</p> Graphical Abstract <p></p>