A PD‐L1 Antibody‐Conjugated PAMAM Dendrimer Nanosystem for Simultaneously Inhibiting Glycolysis and Promoting Immune Response in Fighting Breast Cancer

作者：Peng Zhang, Zhi Li, Weiling Cao, Jingjie Tang, Yi Xia, Ling Peng, Jing Ma · 发表于：Advanced Materials · 年份：2023 · DOI：10.1002/adma.202305215 · 被引用次数：40 · 研究领域：Protein Degradation and Inhibitors、RNA Interference and Gene Delivery、Nanoplatforms for cancer theranostics

Breast cancer is the most frequent malignancy affecting women, yet current therapeutic strategies remain ineffective for patients with late-stage or metastatic disease. Here an effective strategy is reported for treating metastatic breast cancer. Specifically, a self-assembling dendrimer nanosystem decorated with an antibody against programmed cell death ligand 1 (PD-L1) is established for delivering a small interfering RNA (siRNA) to target 3-phosphoinositide-dependent protein kinase-1 (PDK1), a kinase involved in cancer metabolism and metastasis. This nanosystem, named PPD, is designed to target PD-L1 for cancer-specific delivery of the siRNA to inhibit PDK1 and modulate cancer metabolism while promoting programmed cell death 1 (PD-1)/PD-L1 pathway-based immunotherapy. Indeed, PPD effectively generates simultaneous inhibition of PDK1-induced glycolysis and the PD-1/PD-L1 pathway-related immune response, leading to potent inhibition of tumor growth and metastasis without any notable toxicity in tumor-bearing mouse models. Collectively, these results highlight the potential use of PPD as an effective and safe tumor-targeting therapy for breast cancer. This study constitutes a successful proof of principle exploiting the intrinsic features of the tumor microenvironment and metabolism alongside a unique self-assembling dendrimer platform to achieve specific tumor targeting and siRNA-based gene silencing in combined and precision cancer therapy.