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

Breast cancer is the most frequent malignancy affecting women, yet current therapeutic strategies remain ineffective for patients with late-stage or metastatic disease. We report here an effective strategy for treating metastatic breast cancer. Specifically, we established a self-assembling dendrimer nanosystem decorated with an anti-PD-L1 antibody for delivering a small interfering RNA (siRNA) to target PDK1, a protein kinase involved in cancer metabolism and metastasis. This nanosystem (named PPD) was designed to target PD-L1 for cancer specific delivery of the siRNA to inhibit PDK1 (named siPDK1) and modulate cancer metabolism while promoting PD-1/PD-L1 pathway-based immunotherapy. Indeed, PPD effectively protected siPDK1 from degradation and supported its specific delivery to cancer cells for downregulating PDK1 expression. This resulted in 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 tumor microenvironment and metabolism alongside unique self-assembling dendrimer platform to achieve specific tumor targeting and siRNA-based gene silencing in combined and precision cancer therapy. This article is protected by copyright. All rights reserved.