Controlled Delivery of Gasotransmitters for Cardiovascular Therapy: Molecular Mechanisms, Engineered Platforms, and Translational Perspectives

Abstract: Gasotransmitters, including nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H 2 S) exert broad cardioprotective effects by regulating vascular function, inflammatory signaling, oxidative stress, mitochondrial homeostasis, and myocardial remodeling. However, their short half-lives, rapid diffusion, and narrow therapeutic windows limit their clinical translation, making controlled delivery a central challenge for gas-based cardiovascular therapy. This review integrates recent mechanistic insights with advances in delivery engineering to provide a delivery-centric synthesis that links gasotransmitter biology, delivery strategies, and cardiovascular disease applications. We summarize the regulatory roles of NO, CO, and H 2 S in cardiovascular pathophysiology and critically evaluate three delivery strategies designed to address the distinct and competing requirements of gas therapy. Localized in situ platforms improve lesion retention and reduce systemic exposure, systemic nanocarriers enhance donor stability and myocardial accumulation through passive or active targeting, and stimuli-responsive systems enable trigger-regulated gas release in response to pathological cues or external stimuli. Despite these advances, major translational barriers remain, including long-term biosafety, scalable manufacturing, complex pharmacokinetic behavior, and regulatory uncertainty. By integrating disease-stage requirements, release kinetics, myocardial or vascular specificity, and clinical feasibility, this review provides a delivery-centered framework for the rational design and translation of next-generation gasotransmitter therapies for cardiovascular diseases. Keywords: gasotransmitters, molecular mechanisms, controlled release, localized delivery, systemic delivery, stimuli-responsive delivery, cardiovascular therapy