树突状细胞膜杂化纳米疫苗构建及其介导的温热免疫治疗研究

Cancer vaccine can induce antigen specific immune response, which has shown great potential in cancer treatment. As the key factor of vaccine, antigen plays a central role in eliciting antitumor immunity. However, the insufficient antigen delivery, low efficiency of antigen presentation by dendritic cells (DCs), and tumor mutation as well as MHC allelic loss have greatly restricted the therapeutic efficiency of vaccine. In this project, we propose to develop a kind of DC membrane hybrid zinc phosphate nanoparticles based vaccine for tumor prevention and therapy. Owing to the chelating ability of Zn2+, the nanoparticles can coencapsulate multiple neoantigen peptides and melanin with high efficiency. Taking advantage of the homologous targeting ability of DC membrane, this platform can realize the in vivo precise delivery of antigen to DCs. After irradiating by near infrared laser, the induced mild heat would enhance the recruitment of DCs, promote the presentation of multiple neoantigen peptides and migration of primed DC to draining lymph nodes. The corresponding research will exploit the targeting ability, high-efficient antigen presentation and reduced immune tolerance of DC membrane hybrid nanovaccine. It would improve current vaccine therapeutic dilemma and provide a promising strategy for cancer treatment.

肿瘤疫苗通过诱导抗原特异性免疫应答，可有效预防和治疗肿瘤，应用前景广阔。然而，抗原作为疫苗的核心要素，存在体内递送不佳，树突状细胞（DC）对其呈递效率低下，以及易发生突变和表位丢失等问题，极大地阻碍了肿瘤疫苗发挥疗效。因此，本项目拟构筑DC细胞膜杂化羟基磷酸锌纳米粒，利用Zn2+特殊的螯合作用，高效共载多表位新抗原肽和光敏剂黑色素；通过DC细胞膜的同源靶向作用，促进DC对抗原的高效捕获，实现疫苗在体内的精准递送；结合近红外光照射黑色素产生的温和光热，促进DC招募、对多表位新抗原肽的加工处理及向引流淋巴结的归巢，进而提高抗原呈递效率，增强肿瘤特异性免疫应答，减少因抗原调变导致的免疫逃逸。相关研究将探索DC细胞膜杂化纳米疫苗靶向递送特性、抗原高效呈递能力及免疫耐受抑制作用，以期改善现阶段肿瘤疫苗治疗的困境，为肿瘤的有效防治提供创新性的研究策略。

肿瘤疫苗通过诱导抗原特异性免疫应答，可有效预防和治疗肿瘤，应用前景广阔。然而，抗原作为疫苗的核心要素，存在体内递送不佳，树突状细胞（DC）对其呈递效率低下等问题，极大地阻碍了肿瘤疫苗发挥疗效。本项目构筑了DC细胞膜蛋白杂化的羟基磷酸锌纳米粒，利用Zn2+特殊的螯合作用，高效共载抗原多肽和光敏剂黑色素。该纳米疫苗水合粒径约为50nm，zeta电位约为-10mV，显示了良好的生理稳定性。结合近红外照射，该纳米疫苗可诱导有效的体外、细胞内和体内温热效应。该纳米疫苗在体内外均显示了对DC细胞的同源靶向作用，可实现DC对纳米疫苗的高效摄取，同时利用纳米粒的尺寸效应，可有效回流至肿瘤引流淋巴结，实现了疫苗在体内的精准递送。此外，近红外光照射黑色素产生的温和光热，促进了DC对抗原多肽的加工处理，提高了抗原呈递效率。进一步将该纳米疫苗给予MC-38荷瘤小鼠，可有效促进肿瘤引流淋巴结DC细胞的熟化，肿瘤微环境、脾脏和肿瘤引流淋巴结效应T细胞的扩增，提高血液循环中免疫刺激性炎症因子的水平，从而显著抑制肿瘤生长。本研究为肿瘤的有效防治提供了一种创新性的研究策略。