Background:Pharmacologically targeting the STING pathway offers a novel approach to cancer immunotherapy. However, small-molecule STING agonists face challenges such as poor tumor accumulation, rapid clearance, and short-lived effects within the tumor microenvironment, thus limiting their therapeutic potential. To address the challenges of poor specificity and inadequate targeting of STING in breast cancer treatment, herein, we report the design and development of a targeted liposomal delivery system modified with the tumor-targeting peptide iRGD (iRGD-STING-PFP@liposomes). With LIFU irradiation, the liposomal system exploits acoustic cavitation, where gas nuclei form and collapse within the hydrophobic region of the liposome lipid bilayer (transient pore formation), which leads to significantly enhanced drug release.Methods:Transmission electron microscopy (TEM) was used to investigate the physicochemical properties of the targeted liposomes. Encapsulation efficiency and in vitro release were assessed using the dialysis bag method, while the effects of iRGD on liposome targeting were evaluated through laser confocal microscopy. The CCK-8 assay was used to investigate the toxicity and cell growth effects of this system on 4T1 breast cancer cells and HUVEC vascular endothelial cells. A subcutaneous breast cancer tumor model was established to evaluate the tumor-killing effects and therapeutic mechanism of the newly developed liposomes.Results:The liposome carrier exhibited a regular morphology, with a particle size of 232.16 ± 19.82 nm, as indicated by dynamic light scattering (DLS), and demonstrated low toxicity to both HUVEC and 4T1 cells. With an encapsulation efficiency of 41.82 ± 5.67%, the carrier exhibited a slow release pattern in vitro after STING loading. Targeting results indicated that iRGD modification enhanced the system’s ability to target 4T1 cells. The iRGD-STING-PFP@liposomes group demonstrated significant tumor growth inhibition in the subcutaneous breast cancer mouse model with effective activation of the immune system, resulting in the highest populations of matured dendritic cells (71.2 ± 5.4%), increased presentation of tumor-related antigens, promoted CD8+ T cell infiltration at the tumor site, and enhanced NK cell activity.Conclusions: The iRGD-STING-PFP@liposomes targeted drug delivery system effectively targets breast cancer cells, providing a new strategy for breast cancer immunotherapy. These findings indicate that iRGD-STING-PFP@liposomes could successfully deliver STING agonists to tumor tissue, trigger the innate immune response, and may serve as a potential platform for targeted immunotherapy.
背景：靶向STING通路的药物干预为癌症免疫治疗提供了新策略。然而，小分子STING激动剂面临肿瘤蓄积性差、清除迅速及肿瘤微环境内作用时间短等挑战，限制了其治疗潜力。为解决乳腺癌治疗中STING靶向性不足与特异性差的问题，本研究设计开发了经肿瘤靶向肽iRGD修饰的靶向脂质体递送系统（iRGD-STING-PFP@脂质体）。该系统在低频超声辐照下，利用声空化效应使脂质体疏水双层内形成并溃灭的气核产生瞬时孔隙，显著增强药物释放。 方法：采用透射电子显微镜表征靶向脂质体的理化性质，透析袋法测定包封率与体外释放行为，激光共聚焦显微镜评估iRGD对脂质体靶向能力的影响。通过CCK-8法检测该系统对4T1乳腺癌细胞和HUVEC血管内皮细胞的毒性及生长抑制作用。建立皮下乳腺癌荷瘤模型，评估新型脂质体的抑瘤效果与治疗机制。 结果：动态光散射显示脂质体载体形态规整，粒径为232.16±19.82 nm，对HUVEC和4T1细胞均呈现低毒性。STING载药后包封率达41.82±5.67%，体外呈现缓释特性。靶向实验表明iRGD修饰增强了系统对4T1细胞的靶向能力。在皮下乳腺癌小鼠模型中，iRGD-STING-PFP@脂质体组显示出显著的肿瘤生长抑制效果，能有效激活免疫系统：成熟树突状细胞比例最高（71.2±5.4%），肿瘤相关抗原呈递增加，促进肿瘤部位CD8+T细胞浸润，并增强NK细胞活性。 结论：iRGD-STING-PFP@脂质体靶向递药系统能有效靶向乳腺癌细胞，为乳腺癌免疫治疗提供了新策略。该研究表明iRGD-STING-PFP@脂质体可成功递送STING激动剂至肿瘤组织，激活先天免疫应答，有望成为靶向免疫治疗的潜在平台。
肿瘤(癌症)患者之家