Carrier-free Nanotherapeutics unleashed: Ce6/siPD-L1 co-delivery system synergizes photodynamic and RNAi therapies to combat breast cancer

  • Int J Biol Macromol. 2025 Jul;318(Pt 1):144962. doi: 10.1016/j.ijbiomac.2025.144962.
Yingnan Luo  1 ,  Xueyuan Wang  2 ,  Yuting Li  1 ,  Dandan Duan  1 ,  Keyao Liu  1 ,  Meng Lei  3 ,  Liefeng Zhang  4 ,  Yongqiang Zhu  5
Affiliations
  • 1. School of Food and Pharmaceutical Engineering, Nanjing, Normal University, Nanjing 210023, China.
  • 2. College of Life Science, Nanjing Normal University, Nanjing 210023, China.
  • 3. College of Science, Nanjing Forestry University, Nanjing 210037, China.
  • 4. College of Life Science, Nanjing Normal University, Nanjing 210023, China. Electronic address: [email protected].
  • 5. College of Life Science, Nanjing Normal University, Nanjing 210023, China. Electronic address: [email protected].
PMID: 40480558 DOI: 10.1016/j.ijbiomac.2025.144962
Abstract

Small interfering RNA targeting PD-L1 (siPD-L1) demonstrates therapeutic potential in Cancer Immunotherapy, but faces challenges including inefficient lysosomal escape and carrier-induced toxicity. To address these limitations, we developed a carrier-free nanoparticle (NP) system, TPP-Ce6@siPD-L1. The amino-modified triphenylphosphine (TPP) was covalently connected with Ce6 to form an amphiphilic complex, which then loaded siPD-L1 creating an efficient co-delivery system for photosensitizers (PS) and gene drugs. Electrostatic and hydrophobic interactions drove the spontaneous self-assembly of TPP-Ce6 and siPD-L1 into uniform spherical NPs with an average diameter of 190 ± 4.885 nm, achieving siPD-L1 encapsulation and Ce6 loading. These NPs exhibited excellent structural stability in serum over 5 days and rapid cellular uptake (internalization within 2 h), outperforming free siRNA. The mitochondrial targeting of TPP-Ce6 ensures the generation of Reactive Oxygen Species (ROS) within tumor cell mitochondria upon light irradiation, leading to mitochondrial damage and Apoptosis. Simultaneously, the delivery of siPD-L1 effectively silences PD-L1 expression, enhancing immune response through the Cyclic GMP-AMP Synthase (cGAS)-stimulator of interferon genes (STING) pathway (cGAS-STING). This dual-modality platform integrates photodynamic therapy (PDT) and RNA interference (RNAi), offering a novel approach for synergistic Anticancer therapy.

Keywords
Breast cancer; PDT; RNAi; cGAS-STING pathway; siPD-L1.
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