2. Academic Validation
  3. Feedback-Amplified Drug Delivery of αPD-L1-Modified Lipoplatin for Chronological Synergy in NSCLC through PD-L1 Upregulation

Feedback-Amplified Drug Delivery of αPD-L1-Modified Lipoplatin for Chronological Synergy in NSCLC through PD-L1 Upregulation

  • ACS Appl Mater Interfaces. 2025 Oct 8;17(40):55861-55875. doi: 10.1021/acsami.5c12335.
Yi Cen 1,  Xin-Xuan Li 1,  Ying Chen 1,  Xiao-Cheng Ou 1,  Bai-Xue Yu 1,  Xia-Yun Chen 1,  Yi-Bin Liu 2,  Wen-Xiu Qiu 3,  Xin Chen 4,  You-Zhi Tang 2,  Tao Wang 4 5,  Ling-Wen Ding 6,  Shi-Ying Li 1 7 4
Affiliations

Affiliations

  • 1 Fifth Affiliated Hospital, Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou 511436, P. R. China.
  • 2 Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, P. R. China.
  • 3 Institute of Biology and Medicine, College of Life Science and Health, Wuhan University of Science and Technology, Wuhan 430081, P. R. China.
  • 4 Department of Pulmonary and Critical Care Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, P. R. China.
  • 5 State Key Laboratory of Respiratory Diseases, Guangdong Key Laboratory of Vascular Diseases, Guangzhou Institute of Respiratory Health, First Affiliated Hospital, Guangzhou Medical University, Guangzhou 510120, P. R. China.
  • 6 Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119074.
  • 7 Department of Diagnostic Radiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119074.
PMID: 40997865 DOI: 10.1021/acsami.5c12335
Abstract

The limited efficacy of PD-L1 blockade in non-small cell lung Cancer (NSCLC) patients with low PD-L1 expression necessitates the optimization of therapeutic strategies. In this study, we found that PD-L1 expression levels correlate with survival outcomes in αPD-L1-treated NSCLC patients and cisplatin significantly upregulates PD-L1 expression. Building on these findings, PD-L1 antibody-conjugated liposomal cisplatin (αPD-L1@Lipoplatin) is fabricated to integrate chemotherapy-induced PD-L1 upregulation with feedback-enhanced drug delivery and targeted immune checkpoint blockade to enhance NSCLC immunotherapy. Interestingly, the selective targeting ability of αPD-L1@Lipoplatin further upregulates PD-L1 expression, creating a positive feedback loop that continually increases the density of targeting sites and improves drug delivery efficiency. In parallel, αPD-L1@Lipoplatin enhances cytotoxic CD8+ T-cell infiltration, suppresses immunosuppressive regulatory T cells, and increases intratumoral levels of interferon-γ (IFN-γ) and granzyme B, contributing to the chronological synergy between chemotherapy and immunotherapy, thereby boosting the αPD-L1 response and NSCLC inhibition. Importantly, αPD-L1@Lipoplatin effectively suppresses tumor growth without causing significant hepatorenal toxicity, maintaining stable body weight and showing no histopathological abnormalities in major organs. This feedback-amplified drug delivery system offers a promising strategy to enhance drug delivery efficiency and αPD-L1 responsiveness, holding great potential for improving NSCLC immunotherapy.

Keywords

Lipoplatin; NSCLC; feedback-amplified tumor targeting; immune checkpoint blockade therapy; tumor-targeted drug delivery.

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