Molecular weight of hyaluronic acid in nanocarriers

Hyaluronic acid (HA) is widely used in nanomedicine owing to its biocompatibility, receptor-targeting ability, and structural versatility. Among the key design parameters of HA-based nanocarriers, molecular weight (MW) critically influences biological performance; yet the optimal MW remains controversial. Although higher MW is often assumed to enhance CD44 binding and targeting efficiency, evidence indicates that its effects are multidimensional, context-dependent, and frequently non-linear. This review systematically examines how the MW of HA regulates cellular uptake, active targeting, drug solubilization, release kinetics, biodegradation, immunomodulation, and translational potential. At the cellular level, HA MW modulates multivalent CD44 engagement and receptor clustering, often producing a bell-shaped relationship with internalization efficiency. At the tissue level, MW affects tumor accumulation through competing influences on receptor avidity, nanoparticle size, and systemic clearance. Lower-MW HA generally promotes barrier penetration, cellular uptake, and pro-inflammatory responses, whereas higher-MW HA enhances stability, anti-inflammatory signaling, and circulation time but may reduce uptake due to steric hindrance. Overall, optimal MW selection depends on nanocarrier design, disease context, and dominant biological barriers. This review provides a mechanistic framework to guide rational MW selection in next-generation HA-based nanotherapeutics.