Inspired by the natural evolutionutilization of dinitrosyl iron unit for the storage of NO, a chemical library of biomimetic dinitrosyl iron complexes (DNICs) was established for developing NO prodrugs. We next designed tumor-targeted nanocarriers (NanoNO) to stabilize DNICsincrease the tumor accumulation. The proof-of-concept of NanoNO on HCC, PDACGBM murine cancer models revealed that NanoNO can target tumorsstimulate anti-cancer immunity, leading to tumor regression. NanoNO overcomes the bottleneck for translation of NO-related physiology into the biomedical applications, including therapies for various cancersmetabolic syndrome-induced cognitive ability impairment,active ingredients for skincare products.

Combination therapy of NanoNO with chemotherapeutics, protein therapeuticscancer vaccines has been shown to have better efficacy in disease animal models implanted with liver, pancreaticbrain cancer cells than the single treatment. We further developed DNIC-1-OH as the first-in-class prodrug for oral delivery of NO to brain. Steadylocal release of NO from DNIC-1-OH in the brain can last for ~24 h. Codelivery of NOsiRNA against the immune checkpoint to brain tumors increased cytotoxic T cell infiltrationactivation in tumors,suppressed tumor progression. These combination treatments with NanoNO can modulate tumor microenvironmentstimulate anti-cancer immunity, leading to a new horizon of cancer treatment.

NO-related pharmaceuticsbiomaterials for cardiovascular diseases, neurodegenerative disorders, organ transplantations, cancer therapy,etc. were estimated to worth a ~$USD 100 billion in 2024. Biomimetic DNICsDNIC-derived nanomedicine-NanoNO features the advantages in facile synthetic methodology through one-pot reaction, multiple drug administration routes, steady release of NO with half-life as ~1 day, precise delivery of NO, favorable safety profile,wide-spectrum therapeutic activity against cancerneurodegenerative disorders. NanoNO is allowed to combine with various chemotherapeutics, targetedimmune therapeutics to treat liver, pancreatic, brain cancersother highly metastatic cancers.