新辅助放疗作为临床肿瘤综合治疗的重要手段，通过术前干预有效降低肿瘤分期并缩小手术范围，提高治疗效果。然而，新辅助放疗过程中对正常组织的损伤，尤其是对皮肤和粘膜细胞的影响，导致术后创面愈合不良，严重影响患者生活质量。临床现有的辐射防护药物多是手术前预防性使用，尚无专门针对新辅助放疗后手术创面的治疗药物。

辐射影响手术口愈合的机制涉及到多个层面，主要通过活性氧（Reactive oxygen species，ROS）的产生来实现。皮肤细胞在辐射作用下产生大量 ROS，这些高反应性分子与细胞内蛋白质和核酸等生物大分子发生反应，引起结构和功能损伤。同时，激活细胞内凋亡和衰老途径，导致细胞增殖能力下降。这些细胞层面的损伤积累，最终影响组织的修复能力，阻碍伤口的正常愈合。

本论文针对“促进新辅助放疗后手术创面愈合”这一临床需求，基于自组装短肽和透明质酸开发了一种仿生新型载药糖肽水凝胶（CHRgel），由自组装肽（R-peptide）、透明质酸（Hyaluronic acid，HA）和虫草素（Cordycepine，Cor）构成。其中，通过非共价相互作用介导的短肽与透明质酸的共组装，形成由数根纳米纤维沿纵向排列而成的超纤维束糖肽凝胶，通过模拟天然细胞外基质的网络结构，为细胞提供了良好的粘附和增殖环境。短肽中的精氨酸具有抗氧化能力，并能促进内源性一氧化氮（Nitric oxide，NO）的合成，进一步促进伤口愈合。此外，醛基修饰的HA为虫草素提供了动态共价结合位点，能够实现药物的响应性释放，有效抑制了辐射诱导的细胞衰老。综合这些特性，CHRgel 通过抗氧化、抗衰老、促血管新生和促细胞粘附增殖等途径促进新辅助放疗后手术创面的快速愈合。

本研究的成果为新辅助放疗后手术创面愈合提供了一种新的治疗策略，这对于提高患者的生活质量和手术成功率具有重要意义。同时，CHRgel 的成功开发不仅为放疗后伤口愈合的难题提供了解决方案，也为其他难愈合创面用生物材料的研发提供了新的思路和方法。

Neoadjuvant radiotherapy is a critical component of the multimodal oncological treatment paradigm, designed to enhance therapeutic outcomes by downsizing tumors and limiting the surgical resection scope prior to definitive surgery. However, this modality can induce collateral damage to healthy tissues, particularly affecting the integrity of the skin and mucosal cells, which can manifest as impaired postoperative wound healing and a subsequent decline in patient quality of life. The current armamentarium of radioprotective agents is predominantly preventive, aimed at shielding tissues before the surgical procedure, with a dearth of targeted therapeutics specifically engineered for the management of surgical incisions post-neoadjuvant radiotherapy.

The etiology of radiation-induced impairment of surgical wound healing is complex and multifactorial, with the generation of reactive oxygen species (ROS) being a pivotal event. Upon irradiation, skin cells are induced to produce ROS, which are highly reactive and can readily engage in reactions with cellular macromolecules, including proteins and nucleic acids, resulting in their structural and functional impairment. Additionally, ROS can trigger the activation of intracellular apoptotic and senescence pathways, thereby attenuating cellular proliferative capacity. This cascade of cellular insults culminates in a diminished tissue repair capability, which is a critical barrier to effective wound healing.

In this study, we introduce a novel biomimetic glycopeptide hydrogel (CHRgel), synthesized through the co-assembly of self-assembled short peptides and hyaluronic acid, to target the clinical challenge of enhancing surgical incision healing following neoadjuvant radiotherapy. The CHRgel is formulated with self-assembled peptides (R-peptides), hyaluronic acid (HA), and cordycepin (Cor). The co-assembly process, mediated by non-covalent interactions, results in the formation of a supramolecular structure consisting of longitudinally aligned nanofibers, which emulates the natural extracellular matrix and furnishes an optimal milieu for cell adhesion and proliferation.

The R-peptides within the CHRgel possess inherent antioxidant properties and are capable of enhancing the production of endogenous nitric oxide (NO), a known promoter of wound healing. Furthermore, the aldehyde-modified HA within the hydrogel provides a dynamic covalent binding platform for cordycepin, facilitating a responsive drug release mechanism that effectively counters radiation-induced cellular senescence. Collectively, CHRgel exerts its therapeutic effects through a synergistic combination of antioxidant and anti-senescence actions, as well as by promoting angiogenesis and enhancing cell adhesion and proliferation.

The findings of this research delineate a promising therapeutic approach to the healing of surgical incisions following neoadjuvant radiotherapy, with significant implications for bolstering patient quality of life and surgical outcomes. Moreover, the successful development of CHRgel not only addresses the unresolved issue of post-radiotherapy wound healing but also paves the way for innovative biomaterials that could potentially be applied to the management of other recalcitrant wound types.