Advances in Lipid-Polymer Hybrid Nanoparticles: Design Strategies, Functionalization, Oncological and Non-Oncological Clinical Prospects.

Lipid-polymer hybrid nanoparticles (LPHNPs) are the next-generation nanocarriers that integrate the mechanical strength and sustained-release capacity of polymeric cores with the biocompatibility and high drug-loading efficiency of lipid shells. Various design strategies and architectures that enhance encapsulation efficiency, stability, and targeted delivery of diverse therapeutic agents are reviewed. Commonly employed polymers, lipids, and surfactants that enable controlled drug release and enhanced pharmacokinetic performance are summarized in tabular form, while fabrication methods such as single-step, emulsification-solvent evaporation, and microfluidic techniques are discussed for their scalability and reproducibility. The therapeutic potential of LPHNPs in delivering poorly soluble drugs, phytochemicals, and genetic materials achieving synergistic therapeutic outcomes in oncological applications is comprehensively highlighted. The manuscript also includes details on ligand-based functionalization and the integration of imaging and stimuli-responsive elements to enhance targeted delivery and develop multifunctional theranostic LPHNPs systems. Furthermore, non-oncologic applications of LPHNPs in ocular, topical, and oral delivery are discussed, emphasizing their potential in treating inflammatory, infectious, and autoimmune disorders with sustained release and enhanced therapeutic efficacy. Recent patents focusing on improved biocompatibility, dual-drug encapsulation, and mRNA delivery are summarized. However, challenges such as large-scale production, reproducibility, safety, and regulatory standardization must be addressed through quality by design approaches and advanced manufacturing technologies to fully realize the clinical and commercial potential of next-generation LPHNPs.