Breaking biological barriers: Engineering polymeric nanoparticles for cancer therapy

Polymeric nanoparticles (PNPs) have evolved over the past few decades as promising vehicles to deliver drugs to treat cancer. However, their clinical application remains limited mainly due to several biological obstacles. These include rapid clearance from the bloodstream, complex hemorheological dynamics, suboptimal biodistribution, limited tumor accumulation and extravasation, inefficient cellular internalization and trafficking, and offsite toxicity. How can we carefully tune the physicochemical properties of PNPs to break these barriers? This review answers this question by comprehensively and critically examining recent advances and trends in engineering the physicochemical properties of PNPs to enhance their efficacy in cancer drug delivery. It sheds light on the underpinning mechanisms regulated by size, shape, and surface chemistry critical in overcoming heterogeneous biological barriers. Synergistic effects and the interplay between these physicochemical properties are discussed in detail. The types of PNPs, based on form, morphology, and fabrication strategies, are critically reviewed and evaluated according to their physicochemical properties, which directly impact the efficacy of the drug delivery systems and their fate upon administration. The review concludes by proposing design principles and future research directions to enhance the clinical translation of PNPs and their advancement towards more effective cancer treatments.