Hyaluronan nanogel co-loaded with chloroquine to enhance intracellular cisplatin delivery through lysosomal permeabilization and lysophagy inhibition.

Hyaluronan (HA) has been widely used to construct nanocarriers for cancer-targeted drug delivery, due to its excellent biocompatibility and intrinsic affinity towards CD44 that is overexpressed in most cancer types. However, the HA-based nanocarriers are prone to trapping in lysosomes following the HA-mediated endocytosis, which limited the delivered drug to access its pharmacological action sites and subsequently compromised the therapeutic efficacy. To overcome this intracellular obstacle, here we demonstrated the co-loading of chloroquine (CQ) in HA nanogel could efficiently promote the intracellular delivery of cisplatin. The cisplatin coordination with HA generated the nanogel that could also co-encapsulate CQ (HA/Cis/CQ nanogel). Compared with cisplatin-loaded HA nanogel (HA/Cis), HA/Cis/CQ significantly promoted the lysosomal escape of cisplatin as well as enhanced tumor inhibition in the triple-negative breast cancer model. Mechanism studies suggested that co-delivery of CQ not only induced the lysosomal membrane permeabilization but also inhibited the lysophagy, which collectively contributed to the lysosomal instability and cisplatin escape. This HA/Cis/CQ nanogel elicited less toxicity compared with the combination of free Cis and CQ, thus suggesting a promising HA nanocarrier to boost the cisplatin delivery towards cancer-targeted therapy.