Small interfering RNA (siRNA) has been hailed as a "universal key" capable of silencing any disease-causing gene. However, its clinical application has long been constrained by the challenge of delivery: how to safely and precisely transport these fragile molecules to extrahepatic tissues, particularly tumor sites. Traditional approaches rely on complex in vitro encapsulation techniques, which not only entail high costs but also face issues of toxicity and immune clearance.
In a recent breakthrough study published in Science China: Life Sciences, the research team from Nanjing University successfully developed a siRNA targeted delivery system based on "In Vivo Self-Assembled" (IVSA) technology. This system ingeniously converts the human liver into a "biopharmaceutical factory," enabling precise targeting of EGFR-positive tumors and opening a new avenue for cancer gene therapy. Rather than manufacturing "perfect missiles" in vitro, this study introduces precisely engineered genetic "codes" into the body, allowing the liver to produce and assemble these anticancer "weapons" autonomously. This innovative strategy not only demonstrated superior efficacy compared to traditional targeted drugs in multiple EGFR-mutant lung cancer models but also validated its broad-spectrum anticancer potential across various tumor types, including gastric cancer and breast cancer. The highlights of the study are as follows:
1. Multi-Cancer "Pan-Inhibitor": Overcoming Drug Resistance and Applicability Challenges
In cancer treatment, although traditional small-molecule targeted drugs such as gefitinib and osimertinib are initially effective, patients often experience treatment failure due to drug-resistant mutations. The IVSA system established in this study can exert therapeutic effects irrespective of drug-resistant mutations. Based on the principle of RNA interference, this system directly degrades mRNA at the transcriptional level, thereby remaining unaffected by resistance mutations in oncogenes and functioning as a "pan-inhibitor" that stably suppresses target gene expression. More importantly, this system exhibits outstanding cross-cancer versatility—the research team validated its efficient targeted delivery capability in orthotopic models of lung cancer, gastric cancer, and breast cancer, demonstrating robust therapeutic efficacy against tumors of different origins and anatomical locations, indicating its potential applicability across diverse cancer types. In terms of safety, IVSA treatment exhibited potent anticancer activity with negligible off-target toxicity in normal tissues such as the liver, kidney, and lung. This characteristic of "low toxicity with high efficacy" provides an important safety guarantee for clinical translation.
2. From "In Vitro Drug Manufacturing" to "In Vivo Self-Assembly": Transforming the Liver into a Biopharmaceutical Factory
Conventional siRNA drug development relies heavily on artificial synthesis and complex in vitro encapsulation technologies. The IVSA technology proposed by the research team innovatively leverages principles of synthetic biology to reprogram the liver into an "intelligent pharmaceutical factory" through intravenous injection of plasmid DNA. This system comprises three core components: the siRNA expression element, responsible for producing interfering RNA targeting EGFR; the targeting element, which synthesizes a transmembrane protein equipped with the GE11 navigation peptide, conferring tumor-targeting capability to exosomes; and the co-driven promoter element, ensuring the coordinated expression of both components. Upon receiving these genetic instructions, hepatocytes automatically synthesize EGFR siRNA and package it into GE11-tagged small extracellular vesicles (sEVs), which are then secreted into the bloodstream. This "biopharmaceutical" approach offers significant advantages: it utilizes the body's endogenous exosomal transport system, ensuring high biocompatibility; operates at physiological concentration levels, avoiding the toxic side effects of high-dose exogenous substances; and entails low production costs, circumventing complex in vitro synthesis and purification processes.
3. Precision Guidance System: GE11 Peptide Enables Tumor-Specific Targeting
To ensure the precise targeting of the "missiles," the research team introduced the GE11 peptide as a navigation component in the IVSA system. GE11 is a peptide that specifically binds to the epidermal growth factor receptor (EGFR). Unlike its natural ligand EGF, GE11 does not activate tumor growth signaling upon binding but instead focuses on mediating cellular uptake of the carrier. Experimental evidence confirmed that GE11-tagged sEVs exhibited a marked preference for EGFR-positive cancer cells. In co-culture experiments using EGFR-positive H1975 lung cancer cells and EGFR-negative HBE bronchial epithelial cells, GE11-modified sEVs selectively delivered siRNA cargo to tumor cells while being minimally taken up by normal cells. This system enables "on-demand distribution" based on EGFR expression levels in tumor tissues: the higher the EGFR expression, the greater the siRNA enrichment and the more pronounced the therapeutic effect, achieving truly "guided targeting."
This research achievement not only resolves the technical challenge of siRNA delivery but, more importantly, establishes a "plug-and-play" gene therapy platform. In the future, researchers need only replace the siRNA sequence and targeting peptide within the genetic circuit to rapidly develop therapeutic strategies targeting different cancer-driving genes. This modular design offers new possibilities for personalized cancer therapy: it allows for the simultaneous delivery of multiple siRNAs to achieve combination therapy; enables the customization of treatment regimens based on a patient's genotype; and may play a unique role in postoperative adjuvant therapy by eliminating residual micrometastases. From a broader perspective, IVSA technology represents a deep integration of synthetic biology and precision medicine, ushering in a new era of "biopharmaceuticals." This concept of transforming the human body itself into a drug production factory not only has the potential to fundamentally reshape our understanding of drug manufacturing but also provides novel insights for combating major diseases such as cancer.
The corresponding authors of this study include Prof. Chen-Yu Zhang, Prof. Xi Chen, Prof. Chao Yan, and tenure-track Assistant Professor Zheng Fu from the School of Life Sciences at Nanjing University. The first author is Dr. Hongyuan Guo. This work was supported by the National Natural Science Foundation of China, the CAMS Innovation Fund for Medical Sciences, the Jiangsu Provincial Natural Science Foundation for Young Scholars, and the Jiangsu Province Excellent Postdoctoral Program.
Science China Life Sciences
Experimental study