Tumor suppressor protein-inspired peptide for siRNA delivery and synergistic cancer therapy
image: Figure 1: Design, preparation, and therapeutic mechanisms of PPCi NPs. (A) Self-assembly process of PPCi NPs. The opposite electrical properties of PEG- PEI (positively charged) and siRNA (negatively charged) facilitate their electro- static interaction, leading to the formation of PPCi nanoparticles. (B) Schematic illustration of delivery and mechanism of multifunctional drug system. siRNA delivery into the cytosol for the knockdown of the PLK1 gene. The highly cationic nature of the PPCi NPs enhances their endosomal escape feature. The cell’s inward environment provides physicochemical condition changes, which promote the dismantling of the PPCi NPs and the release of the siRNA into the cell’s cytosol. The siRNA achieves PLK1 gene silencing; meanwhile, the p16MIS is carried into the cell’s nucleus and inhibits the binding between CDK-4/6 and Cyclin D, consequently leading to the disruption of the progression of the mi- tosis from the G1 phase to the S phase. The downregulation of PLK1, coupled with the inhibition of the interphase of the mitosis, promotes the apoptosis of tumor cells.
Credit: Milon Essola J, Yang H et al.
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.
- 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.
- 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.”
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Contact the 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
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