Bioresponsive Nanoparticles\nBoost Starvation Therapy\nand Prevent Premetastatic Niche Formation for Pulmonary Metastasis\nTreatment

In the process of tumor metastasis, tumor cells can acquire\ninvasion\nby excessive uptake of nutrients and energy and interact with the\nhost microenvironment to shape a premetastatic niche (PMN) that facilitates\ntheir colonization and progression in the distal sites. Pyruvate is\nan essential nutrient that engages in both energy metabolism and remodeling\nof the extracellular matrix (ECM) in the lungs for PMN formation,\nthus providing a target for tumor metastasis treatment. There is a\npaucity of strategies focusing on PMN prevention, which is key to\nmetastasis inhibition. Here, we design a bioresponsive nanoparticle\n(HP/GU) based on a disulfide-cross-linked hyperbranched polyethylenimine\n(D-PEI) core and a hyaluronic acid (HA) shell with a reactive oxygen\nspecies (ROS)-sensitive cross-linker between them to encapsulate glucose\noxidase (GOX) and a mitochondrial pyruvate carrier (MPC) inhibitor\nvia electrostatic interaction, which reinforces starvation therapy\nand reduces PMN formation in the lungs via inhibiting pyruvate metabolism.\nIn tumor cells, GOX and MPC inhibitors can be rapidly released and\nsynergistically reduce the energy supply of tumor cells by consuming\nglucose and inhibiting pyruvate uptake to decrease tumor cell invasion.\nMPC inhibitors can also reduce ECM remodeling by blocking cellular\npyruvate metabolism to prevent PMN formation. Consequently, HP/GU\nachieves an efficient inhibition of both primary and metastatic tumors\nand provides an innovative strategy for the treatment of tumor metastases.