Engineering delivery platforms for controlled nitric oxide release

Abstract

Nitric oxide (NO) is a versatile gaseous signaling molecule with broad therapeutic potential in cardiovascular regulation, immune modulation, oncology, antibiotics, and tissue regeneration. However, its clinical application is severely constrained by physicochemical limitations, including poor aqueous solubility, rapid degradation, and the lack of spatiotemporal control over its release. To address these challenges, a diverse array of NO donors, ranging from spontaneous-release compounds to stimuli-responsive prodrugs, has been developed, each with distinct advantages and limitations. In this review, we classify representative NO donors into two major categories: unstable donors (e.g., N-diazeniumdiolates, S-nitrosothiols, SIN-1) and stable donors (e.g., O²-protected diazeniumdiolates, protected SIN-1, nitrobenzene derivatives, BNN6). Here, we highlight recent advances in the engineering of delivery platforms, including polymeric nanoparticles, hydrogels, xerogels, liposomes, and various inorganic materials, which enable precise, stimuli-triggered NO release, improved stability, and tissue-specific targeting. By integrating NO donor chemistry with materials design, these platforms offer strong potential for controlled NO-based therapies across a wide range of biomedical applications. We conclude by outlining future directions and key challenges in translating NO delivery systems into clinically viable therapeutics.