针对目标细胞表面特异受体筛选相应配体，以介导载药系统主动寻靶是实现肿瘤靶向治疗的重要策略之一。近期研究发现，跨膜受体Fn14过度表达于胰腺癌等实体瘤，有望成为疾病治疗的潜在靶标。基于此，本项目拟以Fn14胞外半胱氨酸富含区为靶蛋白，经固相合成与"定位折叠"法制备并表征；在此基础上利用"镜像mRNA展示技术"筛选其D型多肽配体并优化；进一步开展D型多肽修饰的载药纳米胶束构建与评价，以期达到：获得具有胰腺癌靶向功能的D型多肽，该多肽高效介导药物定位攻击病灶，有效抑制癌瘤。多肽对蛋白质具有天然的高亲和力和专一性，因此多肽类分子在重大疾病相关蛋白的识别、调控等研究中扮演了重要角色，但天然L型多肽大多易被体内酶降解，生物半衰期短，应用受到限制。本项目基于合成Fn14胞外自稳定的结构域而开展生物稳定型（D型）功能多肽筛选的探索研究，将为跨膜受体识别及其相关疾病诊断与治疗研究提供有益的思路。

One major challenge in tumor therapy is how to selectively deliver anticancer agent to tumor cells.Targeting ligands that confer 'smartness' (biological recognition) to drug-loaded particles play a vital role in the targeted tumor therapy. Recently, the transmembrane receptor Fn14 was found to be overexpressed in pancreatic cancer and other solid tumor cell lines and thus may provide a potential biomarker for diagnosis and treatment. .The proposal aims to obtain biostable, high-affinity peptide ligands of Fn14 that are capable of differentiating the pancreatic cancer cells from normal tissues to achieve specific targeting and enhanced antitumor effect in vitro and in vivo. The first step is preparation of the extracellular cysteine-rich domain of Fn14 as the target protein via solid-phase synthesis and orthogonal folding. The following is to screen and optimize the D-peptide ligands by a novel mirror-image mRNA display technique derived from the combination of mRNA display and 'enantiomer inversion' strategy. And then is the construction of D-peptide modified drug-loaded micelles and therapeutic efficacy evaluation in vitro and in vivo. .Peptides, because of their large interacting surfaces, offer the prospect of enhanced potency, high specificity and low toxicity. However, most bioactive peptides suffer the limitation: poor stability in physiological environments. The biostable functional peptide screening from the synthesized extracellular self-stablized domain of Fn14 protein presented here will provide new ideas for transmembrane receptors recognition and related diseases diagnosis and treatment.