Carbon
monoxide (CO) therapy has become a hot topic in the field
of gas therapy because of its application prospect in the treatment
of various diseases. Due to the high affinity for human hemoglobin,
the main challenge of CO-loaded nanomedicine is the lack of selectivity
and toxicity in the delivery process. Although many commercial CO-releasing
molecules (CORMs) have been widely developed because of their ability
to deliver CO, CORMs still have some disadvantages, including difficult
on-demand controlled CO release, poor solubility, and potential toxicity,
which are limiting their further application. Herein, an X-ray-triggered
CO-releasing nanomicelle system (GW/MnCO@PLGA) based on GdW10 nanoparticles (NPs) (GW) and MnBr(CO)5 (MnCO) encapsulating
in the poly(lactic-co-glycolic acid) (PLGA) polymer
was constructed for synergistic CO radiotherapy (RT). The production
of strongly oxidative superoxide anion (O2
–•) active species can lead to cell apoptosis under the X-ray sensitization
of GW. Moreover, strongly oxidative O2
–• radicals further oxidize and compete with the Mn center, resulting
in the on-demand release of CO. The radio/gas therapy synergy to enhance
the efficient tumor inhibition of the nanomicelles was investigated in vivo and in vitro. Therefore, the establishment
of an X-ray-triggered controlled CO release system has great application
potential for further synergistic RT CO therapy in deep tumor sites.