Tumor suppressor protein-inspired peptide for siRNA delivery and synergistic cancer therapy

In a recent study in Fundamental Research led by Prof. Yuanyu Huang of Beijing Institute of Technology and Prof. Xing-Jie Liang of the National Center for Nanoscience and Technology, a team of researchers developed a novel self-assembled nanoparticle platform named PPCi that overcomes critical delivery barriers in RNA interference (RNAi) therapy while delivering dual anti-tumor actions.

“RNAi therapeutics enables sequence-specific silencing of disease-causing genes at the mRNA level,” explains Huang. “However, while several siRNA-based drugs have been approved for rare hepatic disorders, their application in oncology remains limited due to delivery challenges.”

Notably, unmodified siRNAs are rapidly degraded by nucleases in circulation, exhibit negligible cellular uptake owing to their large size and negative charge, and even when internalized via endocytosis are largely trapped in endosomes. As a result, they cannot access the cytoplasmic RNA-induced silencing complex, which is essential for gene silencing. Among these obstacles, inefficient endosomal escape is widely regarded as the primary bottleneck that limits therapeutic efficacy.

To address these issues, the team designed PPCi by co-assembling a rationally engineered multifunctional peptide, CPP44-RI-p16MIS-4R, with a cationic polymer to deliver siRNA targeting polo-like kinase 1 (PLK1), a master regulator of mitosis that is frequently overexpressed in cancers. The system’s innovation lies in its “two birds, one stone” strategy.

1. The dual-function peptide enables efficient delivery and G1 phase arrest: The CPP44 domain serves as a cell-penetrating peptide that enhances endocytic uptake and promotes tumor-selective accumulation. Fused within the same construct is p16MIS, the minimal inhibitory sequence derived from the tumor suppressor p16, which induces a robust block at the G1/S checkpoint, halting DNA replication and preventing tumor cells from entering the synthesis phase.
2. Synergistic cell-cycle disruption amplifies apoptosis: Following internalization, the cationic polymer component facilitates endosomal escape through the proton sponge effect, releasing siPLK1 into the cytoplasm. There, siPLK1 silences PLK1 expression and arrests cells at the G2/M transition. The concurrent blockade of both G1/S by p16MIS and G2/M by siPLK1 creates a dual-brake effect on the cell cycle, significantly enhancing tumor cell apoptosis beyond what either agent could achieve alone.

“In both in vitro and in vivo models, PPCi demonstrated high gene-silencing efficiency, potent tumor growth suppression, and excellent biocompatibility, significantly outperforming conventional non-viral delivery systems,” shares Liang. “The carrier itself contributes directly to therapeutic activity, transforming the delivery vehicle from a passive shuttle into an active anti-cancer agent.”

“This work redefines what a delivery system can be,” adds Huang. “Instead of being a passive courier, PPCi actively participates in the therapeutic mechanism, making every component count.”

Contact author:

• Yuanyu Huang, School of Life Science, Advanced Research Institute of Multidisciplinary Science, Aerospace Center Hospital, Key Laboratory of Molecular Medicine and Biotherapy, Key Laboratory of Medical, Molecule Science and Pharmaceutics Engineering, Beijing Institute of Technology, Beijing 100081, China, yyhuang@bit.edu.cn
• Xing-Jie Liang, CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, Beijing, 100190, China, liangxj@nanoctr.cn
• Mengliang Zhu, CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, Beijing, 100190, China, zhuml@nanoctr.cn
• Mengjie Zhang, School of Life Science, Advanced Research Institute of Multidisciplinary Science, Aerospace Center Hospital, Key Laboratory of Molecular Medicine and Biotherapy, Key Laboratory of Medical, Molecule Science and Pharmaceutics Engineering, Beijing Institute of Technology, Beijing 100081, China, zmj@bit.edu.cn

Funder: 

This work was supported by the National Natural Science Foundation of China (32101148, 32171394, 82102204), Beijing Nova Program (Interdisciplinary Cooperation Project) from Beijing Municipal Science & Technology Commission (20220484207), National Key Research & Development Program of China (2021YFA1201000, 2021YFE0106900, 2023YFC2605003), National Natural Science Foundation of China (NSFC) key project (32030060), NSFC international collaboration key project (51861135103), the Science Fund for Creative Research Groups of Nature Science Foundation of Hebei Province (B2021201038). The authors also thank the CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, and the Biological and Medical Engineering Core Facilities and Analysis & Testing Center, Beijing Institute of Technology, for supporting experimental equipment, and staffs for valuable help with technical support. 

Conflict of interest:

The authors declare that they have no conflicts of interest in this work.

See the article:

Milon Essola J, Yang H et al. Tumor Suppressor Protein-Inspired Peptide for siRNA Delivery and Synergistic Cancer Therapy. Fundamental Research, Volume 5, Issue 2, September  2025, Pages 1920-1929, https://doi.org/10.1016/j.fmre.2025.03.006