Lipid nanoparticles are a clinically validated platform for delivering nucleic acids, but performance is constrained by multiscale physiological barriers spanning circulation, vascular interfaces, extracellular matrices, cellular uptake, and intracellular trafficking. This review links composition–structure–function relationships for ionizable lipids, helper phospholipids, cholesterol, and PEG-lipids to systemic fate, endothelial access, endosomal escape, cytoplasmic stability, and nuclear transport. We outline strategies for tissue and cell targeting, including hepatocyte ligands, immune and tumor selectivity, and selective organ targeting through compositional tuning, together with approaches that modulate escape using pH-responsive chemistries or fusion-active peptides and polymers. We further examine immunomodulatory co-formulation, route and schedule effects on biodistribution and immune programming, and manufacturing and stability levers from microfluidic mixing to lyophilization. Across these themes, we weigh trade-offs between stealth and engagement, potency and tolerability, and potency and manufacturability, noting that only a small fraction of endosomes supports productive release and that protein corona variability and repeat dosing can reshape tropism and clearance. Convergence of standardized assays for true cytosolic delivery, biomarker-guided patient selection, and robust process controls will be required to extend LNP therapeutics beyond the liver while sustaining safety, access, and scale.

The tumor microenvironment (TME) acts as a major barrier to effective drug delivery and contributes to drug resistance in solid tumors. Hypoxia, acidosis, and elevated interstitial fluid pressure limit drug penetration, while cancer-associated fibroblasts and immunosuppressive cells promote survival signaling, drug efflux, and metabolic adaptation. Polymeric drug delivery systems offer a promising strategy to address these barriers because their structures can be precisely engineered and designed to respond to TME-specific stimuli. These properties enable controlled drug release at tumor sites and help improve therapeutic efficacy while reducing systemic limitations. This review discusses how physicochemical and cellular components of the TME contribute to drug resistance and how polymeric nanomedicines can be designed to overcome these barriers. In addition, it examines key challenges that limit clinical translation, including tumor heterogeneity, variable enhanced permeability and retention effects, manufacturing scalability, and regulatory requirements. Finally, this review highlights the future direction of polymer nanomedicine and focuses specifically on developing rational material design, enhancing preclinical models, and developing clinically appropriate strategies to combat TME-mediated drug resistance.

Targeted drug delivery remains difficult because multiple biological barriers interfere with the stable transport of therapeutics to the site of action. Polymeric nanocarriers have gained broad attention as delivery platforms since their composition and surface properties can be adjusted to improve circulation behavior and cellular delivery. This review discusses the major biological barriers involved in targeted drug delivery and describes how polymeric nanocarriers are engineered to overcome them. Major carrier types, including polymeric nanoparticles and micelles, are considered with emphasis on their physicochemical and interfacial features. Particular attention is given to surface engineering and stimuli-responsive design as key strategies for barrier transport and controlled cargo release. The review also highlights representative applications in anticancer, gene, protein, and vaccine delivery, together with translational issues such as biocompatibility, stability, reproducibility, scale-up, and regulatory acceptance.