Multi-nanocarrier Strategy for Light-Activated Nitric Oxide Release: Ruthenium Nitrosyl Complexes in Liposomes, Micelles, and Niosomes for Cancer Therapy

Nitric oxide (NO), once regarded solely as an atmospheric pollutant, is now widely recognized for its important therapeutic functions in biological systems. However, several challenges limit its direct medical use, such as its short half-life, the non-biocompatibility of several NO donors, and their uncontrolled release patterns. To address these challenges, a series of nanomaterials, including vesicles, micelles, and niosomes, have been developed to incorporate a newly synthesized amphiphilic ruthenium nitrosyl (Ru-NO) complex as a versatile photoactivatable NO donor. Notably, this is the first report of encapsulating this amphiphilic Ru-NO complex designated as <b>1·NO</b>, in niosomes (termed <b>1·NO-Nio</b>) for phototriggered NO delivery. The release kinetics and quantum yield of <b>1·NO</b>, as well as its nanoencapsulated forms <b>1·NO-Ves</b>, <b>1·NO-Mic</b>, and <b>1·NO-Nio</b>, were evaluated using UV-vis spectroscopy, Griess assay, and 4-amino-5-methylamino-2',7'-difluorescein diacetate (DAF-FM DA) fluorescence under blue light irradiation (420 nm). Free <b>1·NO</b> released a significant amount of NO (11 μM), whereas encapsulation within nanocarriers resulted in a more controlled and prolonged NO release, with release rates (<i>k</i>_NO) of 0.0093, 0.0065, and 0.0025 min^-1 for <b>1·NO-Ves</b>, <b>1·NO-Mic</b>, and <b>1·NO-Nio</b>, respectively. All three nanocarrier-based nitric oxide (NO) delivery systems demonstrated pronounced, light-activated anticancer activity in vitro tests against the 4T1 breast cancer cell line, with the liposome-based formulation (<b>1·NO-Ves</b>) exhibiting the strongest therapeutic efficacy. These results underscore how distinct nanomaterial platforms can have a significant influence on the nitric oxide (NO) release behavior of a photocontrollable ruthenium nitrosyl (Ru-NO) complex. This underlines the critical role of nanocarrier design in optimizing the performance of photoactivated NO donors for cancer therapy.