O Economizer for Inhibiting Cell Respiration To Combat the Hypoxia Obstacle in Tumor Treatments

Hypoxia, a ubiquitously aberrant phenomenon implicated in tumor growth, causes severe tumor resistance to therapeutic interventions. Instead of the currently prevalent solution through intratumoral oxygen supply, we put forward an "O-economizer" concept by inhibiting the O consumption of cell respiration to spare endogenous O and overcome the hypoxia barrier. A nitric oxide (NO) donor responsible for respiration inhibition and a photosensitizer for photodynamic therapy (PDT) are co-loaded into poly(d,l-lactide- co-glycolide) nanovesicles to provide a PDT-specific O economizer. Once accumulating in tumors and subsequently responding to the locally reductive environment, the carried NO donor undergoes breakdown to produce NO for inhibiting cellular respiration, allowing more O in tumor cells to support the profound enhancement of PDT. Depending on the biochemical reallocation of cellular oxygen resource, this O-economizer concept offers a way to address the important issue of hypoxia-induced tumor resistance to therapeutic interventions, including but not limited to PDT.