Nitric oxide (NO), an endogenous, free radical, highly unstable, diatomic gaseous molecule, plays crucial roles in several physiological and pathological processes. It has attracted broad interest in scientific com-munities due to its involvement in controlling numerous biological processes, such as vasodilation, neu-rotransmission, wound healing, angiogenesis, bone metabolism, apoptosis, insulin secretion, and platelet aggregation inhibition. NO can be protective or destructive, depending on its concentration, exposure time, location, and cellular environment. However, NO gas has a limited ability for effective accumulation and regulated long-term release at certain places, which might have possible side effects. Thus, several classes of NO-releasing molecules (NORMs) or NO donors are widely developed and tested for various clinical and therapeutic applications. However, managing the long-term and controlled release of NO are still challenging. Therefore, the main interest of researchers is the development of various NORMs for sustained NO delivery to a specific biological target site. Several techniques, such as ultrasound, UV-visible, near-infrared (NIR), and X-ray irradiation, can be applied for controllable NO-release from NORMs. This review comprehensively discussed the current development and challenges of the tradi-tional NORMs, such as organic nitrates, nitrites, and inorganic metal complexes, as well as advanced NORMs based on the novel nanocarrier, API drugs (hybrid drugs), and synthetic and biodegradable poly-meric matrices for target-specific controlled NO-delivery. We mainly focused on the present and past views of the NORMs for precise biological and therapeutic applications and discussed their future perspectives.(c) 2023 Elsevier B.V. All rights reserved.
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