Light- and ROS-responsive nanomicelles enable targeted combination photothermal molecular therapy in melanoma cells...

Stimuli-responsive nanocarriers that respond to both exogenous and endogenous cellular stimuli are highly desirable to enable high payload delivery. Here, we designed novel micelles that are responsive to multiple stimuli, including light (exogenous) and reactive oxygen species (ROS, endogenous). We showed that this dual-stimuli response of light and ROS-responsive micelles (LRMs) can be leveraged to reverse the resistance of melanoma cells to a small molecule drug, trametinib. LRMs were designed with hyaluronic acid (HA) that specifically targets CD44 receptors in B16F0 melanoma cells and spheroids. HA was conjugated to IR780, a dye that absorbs near-infrared light and converts it to heat enabling photothermal therapy (PTT). LRMs also incorporated a cleavable thioketal linker that responds to ROS and enables drug delivery at sites of high ROS. Our findings show that trametinib-loaded LRMs function based on a two-step mechanism, enabling combination photothermal molecular therapy that facilitates (i) high short-term cancer cell death, (ii) reduction in the long-term proliferative capacity of cancer cells, (iii) significantly decreased glycolytic function and overall survival, (iv) pronounced downregulation of phosphorylated ribosomal protein S6, and (v) significant metabolic shift in the lipid profile and downregulation of oncometabolites that promote cell growth and proliferation. Furthermore, our results also show that LRM treatment has distinct effects in lipid remodelling and triglyceride storage in 2D cells compared to 3D spheroids, emphasizing the importance of both cellular models in understanding treatment response. Our findings will ultimately enable a new generation of stimuli-responsive nanocarriers that will have a tremendous impact on many diseases beyond cancer.