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

Abstract 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.