Polymer-based nanocarriers for targeted drug delivery: Design, manufacturing, and clinical translation

The polymer-based nanocarriers are more promising and versatile platforms for targeted delivery of drugs because of their ability to overcome several drawbacks of current drugs such as low systemic bioavailability, non-specific biodistribution, rapid clearance from the circulation, and poor solubility. The review critically discusses the design principles, manufacturing strategies and clinical translation of major polymeric nanocarrier systems such as polymeric nanoparticles, micelles, dendrimers, nanogels, and polymersomes with a special focus on structure–property relationships that control their physicochemical properties, biodistribution, and kinetics of drug release. The review also covers the benefits and challenges of targeting by ligands and stimuli-responsive systems in the context of their preclinical success and translational obstacles. Further, the use of passive targeting is limited because of significant interpatient and tumor-specific variation in enhanced permeability and retention (EPR) effect. Although recent advances in fabrication technologies such as microfluidics and continuous manufacturing have enhanced process control and reproducibility, there are still challenges related to the industrial scale implementation, standardization and regulatory compliance. The critical quality attributes of the particle size, surface charge, encapsulation efficiency, and release behavior are also discussed in relation to the therapeutic performance in this review. They discuss their biomedical applications, such as cancer therapy, gene delivery, targeting to the central nervous system, and theranostics, as well as major translational challenges including biological sequestration, long-term toxicity, polymer accumulation, degradation-induced immunogenicity and lack of reproducibility of manufacturing. Although significant preclinical advances have been made, relatively limited number of polymeric nanomedicines have reached the clinical development stage. Future opportunities include emerging trends like the use of hybrid nanocarriers, the development of multifunctional systems, and the application of AI to optimize formulation design, but these will require comprehensive validation, availability of data, and regulatory approval. Overall, polymer based nanocarriers are an important but clinically limited platform that requires addressing of biological, manufacturing and regulatory limitations.