Advancements in Polymer-Based Nanocarriers for Controlled Release of Nitric Oxide: Clinical Applications and Future Prospects

Haizhou Ying,1,* Chao Zhou,2,* Xiankun Liu,3,* Shu Qin,3 Lin Chen,3 Yijun Yu,1 Linying Xia,1 Hongming Lin,3 Songou Zhang,4 Hengguo Long,3 Wenqing Liang1,3 1Medical Research Center, Zhoushan Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, Zhoushan, 316000, People’s Republic of China; 2Department of Orthopedics, Daishan Guanghua Hospital, Zhoushan, Zhejiang, 316000, People’s Republic of China; 3Department of Orthopedics, Zhoushan Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, Zhoushan, 316000, People’s Republic of China; 4School of Medicine, Ningbo University, Ningbo, 315000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hengguo Long; Wenqing Liang, Department of Orthopaedics, Zhoushan Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, 355 Xinqiao Road, Dinghai District, Zhoushan, Zhejiang, 316000, People’s Republic of China, Tel +86-580-8123686 ; +86-580-2615027, Fax +86-580-2616545, Email [email protected]; [email protected]: The clinical management of bone defects presents a significant challenge in regenerative medicine due to the limited self-repair capacity of bone tissue and inadequate vascularization. Nitric oxide, a gaseous signaling molecule, has garnered attention as a potent modulator of bone remodeling, exhibiting pro-osteogenic, pro-angiogenic, and anti-inflammatory properties. However, its therapeutic application is limited by its short half-life, high reactivity, and dose-dependent biphasic effects. Advanced polymer-based nanoformulations have been developed to address these challenges and enable controlled and localized NO delivery to bone tissue. This review explores role of NO in bone repair mechanisms and the limitations of conventional delivery systems. Significant focus is given to innovative polymeric platforms, such as dendrimers, micelles, nanogels, and hybrid composites, which offer precise control over release kinetics, high encapsulation efficiency, and targeted delivery. Additionally, integrating NO delivery within nanoengineered scaffolds and coatings for orthopedic implants is explored as a promising strategy to enhance osteointegration and reduce the risk of post-surgical infections. Preclinical studies demonstrate promising osteogenic effects yet face significant challenges including cytotoxicity at elevated NO concentrations along with non-standardized evaluation protocols and scalability limitations. Future perspectives point to the potential of stimuli-responsive systems, co-delivery approaches, and personalized strategies utilizing additive manufacturing technologies. This review consolidates the latest advancements in the field, underscoring the significant potential of polymer-based NO nanoformulations to revolutionize bone tissue engineering.Keywords: nitric oxide, polymeric nano formulations, bone regeneration, controlled release, nanotechnology and osteogenesis