Hyaluronic acid based functionalization of nanodelivery systems: A promising strategy for CD44-receptors-mediated targeted therapy of lung cancer

Lung cancer (LC) remains the leading cause of cancer-related fatalities in both men and women owing to its enormous potential for metastasis, chemoresistance, and recurrence. Despite the availability of various treatment options, the prevalence of LC is continuously escalating, further challenged by poor patient compliance. Nanotechnology has revolutionized many fields, including the pharmaceutical industry due to the nanoscale dimensions of nanomaterials, their surface chemistry, high encapsulation efficiency, protection of encapsulated drug(s), and controlled release of therapeutic payload. A variety of nanodelivery systems have been designed for both passive and active targeting of LC; however, this review primarily focuses on CD44 (cluster differentiation-44)-receptor-mediated specific targeting using hyaluronic acid (HA)-functionalized nanodelivery systems for the treatment of LC. The rationale of this study is to critically discuss and evaluate the biopharmaceutical and therapeutic potential of various HA-functionalized nanodelivery systems for the treatment of LC while mitigating their off-target effects. The selective targeting and anticancer efficacy of HA-functionalized nanodelivery systems can be further optimized by hybridizing them with additional targeting functionalities such as passive (e.g., PEGylation), active (e.g., conjugation of targeting ligands), and/or stimuli-responsive (e.g., pH, redox, light, temperature) attributes. These adaptations in the design of HA-functionalized nanodelivery systems have demonstrated promising improvements in the therapeutic outcomes for LC; however, sufficient in vitro/in vivo correlations and long-term safety investigations in animal models are essential before these systems can be successfully translated for clinical testing in humans.