Self-targeting carrier-free coordination nanotherapeutics for tumor microenvironment modulation and enhanced chemo-dynamic oncotherapy

Reactive oxygen species (ROS)-based emerging antitumor modality had garnered increasing attentions. Nevertheless, the low delivery efficiency and poor selection of chemotherapeutic agents, and hypoxia and elevated glutathione (GSH) in the tumor microenvironment (TME) had severely restricted the therapeutic efficacy. Herein, we designed a carrier-free self-targeting nanotherapeutic PEM-Cu^II-MET (PCM), which was obtained through coordination-driven self-assembly of the pemetrexed (PEM, a dual-acting small molecule drug), Fenton-like agent copper ion (Cu^Ⅱ), and metformin (MET, a mitochondrial respiratory inhibitor). Through the folate receptor of tumor cells and TME stimulations (lysosomal acid and overexpressed GSH), PCM could efficiently accumulate in tumor regions and internalize into tumor cells followed by rapid drug disassembly. The released MET could significantly inhibit the consumption of O₂ to relieve tumor hypoxia by suppressing mitochondrial respiration. Additionally, oxygen-enriched environment could elevate H₂O₂ content through the reaction of nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOXs) and superoxide dismutase (SOD). Meanwhile, the released Cu^Ⅱ facilitates the depletion of GSH, which could boost ROS accumulation to improve the efficacy of chemodynamic (CDT). In summary, such nanotherapeutic that achieves multiple ROS amplification could improve TME and enhance CDT oncotherapy.