Details

Autor(en) / Beteiligte

• Wang, Xiaoxuan
• Li, Fangxuan
• Zhang, Jialu
• Guo, Lu
• Shang, Mengmeng
• Sun, Xiao
• Xiao, Shan
• Shi, Dandan
• Meng, Dong
• Zhao, Yading
• Jiang, Chao
• Li, Jie

Titel

A combination of PD-L1-targeted IL-15 mRNA nanotherapy and ultrasound-targeted microbubble destruction for tumor immunotherapy

Ist Teil von

• Journal of controlled release, 2024-03, Vol.367, p.45-60

Ort / Verlag

Netherlands: Elsevier B.V

Erscheinungsjahr

2024

Quelle

Access via ScienceDirect (Elsevier)

Beschreibungen/Notizen

• PD-1/PD-L1-based immune checkpoint blockade therapy has shown limited benefits in tumor patients, partially attributed to the inadequate infiltration of immune effector cells within tumors. Here, we established a nanoplatform named DPPA/IL-15 NPs to target PD-L1 for the tumor delivery of IL-15 messenger RNA (mRNA). DPPA/IL-15 NPs were endowed with ultrasound responsiveness and contrast-enhanced ultrasound (CEUS) imaging performance. They effectively protected IL-15 mRNA from degradation and specifically transfected it into tumor cells through the utilization of ultrasound-targeted microbubble destruction (UTMD). This resulted in the activation of IL-15-related immune effector cells while blocking the PD-1/PD-L1 pathway. In addition, UTMD could generate reactive oxygen species (ROS) that induce endoplasmic reticulum (ER) stress-driven immunogenic cell death (ICD), initiating anti-tumor immunity. In vitro and in vivo studies revealed that this combination therapy could induce a robust systemic immune response and enhance anti-tumor efficacy. Thus, this combination therapy has the potential for clinical translation through enhanced immunotherapy and provides real-time ultrasound imaging guidance. [Display omitted] •DPPA/IL-15 NPs maximized on targeting PD-L1 for IL-15 mRNA delivery and demonstrated efficient antitumor effect.•We verified that combination therapy could significantly increase ROS and ER stress, thereby inducing ICD.•Unlike other studies where UTMD is applied, here it served as the first step in initiating anti-tumor immunity.