Tian Jilai, Wan Shixiao, Yang Zhen, Wang Mengting, Zhou Wenzhao, Wo Guanqun, Fu Shuping, Zheng Shiya, Zhou Gaoxin, Hu Xiaomin, Guo Yichen, Guo Jun
Department of Biochemistry and Molecular Biology, School of Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, P. R. China.
Department of Integrated Chinese and Western Medicine, School of Chinese Medicine & School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, P. R. China.
Adv Healthc Mater. 2024 Dec;13(31):e2400030. doi: 10.1002/adhm.202400030. Epub 2024 Aug 7.
Programmed death (PD) 1/PD ligand 1 (PDL1) inhibitors are immune checkpoint inhibitors (ICIs) that may facilitate HER2-positive breast cancer treatment; however, their clinical efficacy remains elusive. Oxygen-enhanced photodynamic therapy (PDT) increases immunogenic cell death (ICD), providing a promising strategy to render the tumor microenvironment more sensitive to the ICIs. Lipid-encapsulated oxygen nanobubbles (Lipo-NBs-O) obtained using nanobubbles (NBs) water for oxygen delivery in vivo can facilitate enhanced PDT. Here, dual-receptor targeted Lipo-NBs-O (DRT@Lipo-NBs-O) is prepared by modifying Lipo-NBs-O with anti-PDL1 scFv and the fusion protein anti-HER2 scFv-tandem-repeat cytochrome c (anti-HER2-nCytc). Copper phthalocyanine is the photosensitizer (PS). DRT@Lipo-PS-NBs-O plus near-infrared irradiation leads to robust ICD induction, increasing DC activation and CD8 T-cell numbers. Modification with anti-PDL1 scFv improves tumor distribution of DRT@Lipo-PS-NBs-O and plays the ICI role, invigorating CD8 T cells and boosting the effects of immunotherapy. Oxygen supplied through DRT@Lipo-PS-NBs-O reduces P-glycoprotein expression. Enhanced PDT and Cytc can cause tumor cell death, thereby reducing the immune burden. Under dual receptor targeting and laser local irradiation, tumor cells become subject to the combination effects of PDT, ICD, ICIs, and apoptosis; this effectively suppresses tumor growth and metastasis. Lipo-NBs-O affords a combination of oxygen delivery and multidrug therapy to alleviate HER2-positive breast cancer.
程序性死亡（PD）1/PD配体1（PDL1）抑制剂是一类免疫检查点抑制剂（ICI），可能有助于HER2阳性乳腺癌的治疗；然而，其临床疗效仍不明确。氧增强光动力疗法（PDT）可增加免疫原性细胞死亡（ICD），为使肿瘤微环境对ICI更敏感提供了一种有前景的策略。使用纳米气泡（NBs）水制备的脂质包裹氧纳米泡（Lipo-NBs-O）用于体内氧输送，可促进增强型PDT。在此，通过用抗PDL1单链抗体片段（scFv）和融合蛋白抗HER2 scFv-串联重复细胞色素c（抗HER2-nCytc）修饰Lipo-NBs-O，制备了双受体靶向Lipo-NBs-O（DRT@Lipo-NBs-O）。铜酞菁作为光敏剂（PS）。DRT@Lipo-PS-NBs-O加近红外照射可导致强大的ICD诱导，增加树突状细胞（DC）激活和CD8 T细胞数量。用抗PDL1 scFv修饰可改善DRT@Lipo-PS-NBs-O在肿瘤中的分布，并发挥ICI作用，激活CD8 T细胞并增强免疫治疗效果。通过DRT@Lipo-PS-NBs-O提供的氧可降低P-糖蛋白表达。增强型PDT和细胞色素c可导致肿瘤细胞死亡，从而减轻免疫负担。在双受体靶向和激光局部照射下，肿瘤细胞受到PDT、ICD、ICI和凋亡的联合作用；这有效地抑制了肿瘤生长和转移。Lipo-NBs-O提供了氧输送和多药治疗的组合，以缓解HER2阳性乳腺癌。
