基于治疗-监测一体化的声-光双模态上转换仿生纳米粒子实现斑块内弱紫外辐照稳定动脉粥样硬化斑块的研究

动脉粥样硬化（AS）是脂质驱动的全身炎性病变，斑块内抗AS作用的M2表型巨噬细胞（Mψ）极化及其胞葬受抑制，导致促炎-抗炎失衡和坏死碎片清除减少，引发斑块不稳定。促进斑块内炎症消退是稳定斑块的新热点。课题组前期发现弱紫外辐照Mψ可抑制多种促炎因子的表达并上调M2极化诱导因子，因此本项目提出斑块内弱紫外按需辐照可促进M2极化和胞葬作用从而稳定斑块的新思路。通过制备核壳型上转换粒子，连接miR的检测探针，并以中性粒细胞膜包被构建上转换仿生纳米粒子。在高脂喂养ApoE-/-小鼠模型上，利用中性粒细胞膜仿生靶向和超声靶向微泡破坏作用，辅助构建的纳米粒子进入AS斑块，不仅实现体表近红外激发的远程弱紫外辐照，还可以体表超声实现示踪及斑块内粒子浓度计算，并按需调整激发光能量，而在体检测miR-155可作为监测Mψ极化状态和胞葬活性的标记物，实现多模态治疗-监测一体化。该方法可望成为稳定AS的新措施。

Atherosclerosis is a lipid-driven chronic and systematic disease. Along with its progression, the micro-environment alteration inhibits M2 phenotype polarization of the macrophages inside the atherosclerotic plaques. Efferocytosis, a process to clear the cell debris mainly by M2 macrophage phagocytosis, is hampered at the advanced plaques, accompanied by the upregulation of pro-inflammatory cytokines and downregulation of the anti-inflammatory cytokines. The imbalance between the pro- and anti-atherosclerotic effects will cause the instability or even rupture of plaques. In lieu of anti-inflammation within the plaques, promoting inflammation resolution has become the new strategy to atherosclerosis. A pilot study from our group demonstrated low-level ultraviolet could suppress the expression of pro-inflammatory cytokines and promote M2 phenotype inducing cytokines. Thus, we hypothesize that intra-plaque ultraviolet low-level radiation could prompt M2 polarization and efferocytosis to stable the plaques. However, the ultraviolet cannot penetrate the skin or blood flow efficiently. In order to fulfill the proposed regime, core-shell upconversion nanoparticles loaded with fluorescent miroRNA detecting probe will be prepared first. Then these particles will be embedded with neutrophil membranes to finalize the bionic upconversion nanoparticles (bio-UCNP). The neutrophil membrane can lend the targeting capacity to atherosclerotic plaque biomimetically. Combined with the ultrasound targeted microbubble destruction effect, the bio-UCNP would be enriched into the plaques. Since the mesoporous silica shell provides excellent acoustic enhancement, the bio-UCNP can be traced by ultrasound. The concentration of bio-UCNP within the plaques could also be calculated according to acoustic intensity- bio-UCNP concentration curve. The inciting light could thus be adjusted according to incite-excite power curve. This is essential to make the radiation tunable at low-level energy to maintain the beneficial bioeffects. That is, the on-demand intra-plaque low-level ultraviolet radiation could be realized with the remote near infrared light through the upconversion effect. Moreover, the macrophage polarization and the efferocytosis status could be monitored in vivo dynamically by the FRET-based miR-155 probe loaded in the bio-UCNP. As a result, the therapy and monitoring process will be integrated in one system by the multi-functional and multi-modal bio-UCNP. This photo therapy with support from the ultrasound to facilitate intra-plaque low-level ultraviolet radiation with the upconversion based therapy-monitoring nanoparticle complex would be a new paradigm of atherosclerotic plaques stabilization.