Key Takeaways & Executive Findings
- •• • In vivo tumor inhibition rate exceeded 70% in the G8 group, significantly outperforming controls, demonstrating potent antitumor efficacy of in situ generated Fm-COPs. • • The dual-lock system requires both AzoR and NTR for activation, ensuring high tumor specificity and minimizing off-target effects, as evidenced by negligible systemic toxicity. • • ICP-MS analysis showed rapid clearance of Sc(OTf)3 from blood (nearly undetectable within 36 h) and near-complete elimination from organs by day 21, indicating acceptable biosafety for the catalytic system. • • Histopathological and blood biochemical analyses revealed no observable damage to major organs, with liver and kidney function indices comparable to PBS controls, supporting the clinical translational potential of this strategy.
Abstract
Therapeutic biosynthesis is a promising strategy for precision cancer therapy, yet achieving controlled synthesis of abiotic materials within tumors remains challenging. Here, we report a “dual lock-and-key” system for tumor-specific intracellular synthesis. The precursor, termed “dual-lock,” is activated by two endogenously overexpressed enzymes—azoreductase (AzoR) and nitroreductase (NTR)—acting as “dual keys” in target cancer cells. This activation triggers a condensation reaction that produces fibrous mesh covalent organic polymers (Fm-COPs) in situ. Synthesized Fm-COPs effectively disrupt the cytoskeleton, inhibiting cell migration and invasion while inducing apoptosis. In vivo studies demonstrate that this strategy achieves specific tumor enrichment and deep penetration, leading to significant tumor growth inhibition (tumor inhibition rate >70%) without systemic toxicity, as evidenced by stable body weights and normal histopathology. The dual enzyme-responsive mechanism ensures high selectivity, and the small-molecule precursors facilitate efficient tumor penetration. This work presents a next-generation approach for high-precision cancer therapy, offering a biocompatible and autonomous strategy for intracellular synthesis.
1. Introduction
Conventional chemotherapy remains the cornerstone of cancer management, yet its efficacy is often compromised by systemic toxicity, multidrug resistance, and suboptimal pharmacokinetics. Nanomedicine has sought to improve drug delivery, but clinical translation is hindered by low drug-loading efficiency, rapid clearance of small nanoparticles, and poor tumor penetration of larger carriers. These limitations underscore the urgent need for therapeutic platforms that are both biocompatible and capable of overcoming biological barriers to achieve deep tumor accumulation.
Intracellular synthesis offers a transformative approach by generating functional biomaterials directly within cells, enabling precise regulation of cellular processes. However, existing strategies often rely on external triggers such as light, which can cause collateral damage, or lack tumor specificity. The “dual lock-and-key” system addresses these bottlenecks by exploiting endogenous enzymes overexpressed in cancer cells to activate precursor molecules, leading to localized synthesis of therapeutic polymers. This autonomous, enzyme-responsive mechanism ensures high selectivity and deep tumor penetration, providing a promising solution for high-precision cancer therapy.
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Hanbin Xu, Mengli Liu, Mengqi Zhao, Mingjie Ye, Yating Gao, Chengye Xi, Yunqing Cao, Junjie Yu, Mahmoud Elsayed Hafez, Ruocan Qian, Binbin Chen, Dawei Li (2026). A “dual lock-and-key” engineered intracellular synthesis for high-precision cancer therapy. SCIENCE CHINA Materials. https://doi.org/10.1007/s40843-025-4129-y
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Frequently Asked Questions
What is the specificity of the dual-lock system, and how does it prevent activation in normal cells?
The dual-lock system requires the simultaneous presence of both azoreductase (AzoR) and nitroreductase (NTR), which are overexpressed in tumor cells but present at low levels in normal tissues. This dual-enzyme requirement ensures that the precursor is only activated in the tumor microenvironment, minimizing off-target effects.
What is the in vivo clearance profile of the catalytic metal Sc(OTf)3, and does it pose long-term toxicity risks?
ICP-MS analysis showed that blood Sc3+ levels decreased rapidly and became nearly undetectable within 36 hours after a single administration. Biodistribution studies revealed transient accumulation in the liver and spleen, with near-complete elimination by day 21. Repeated administration under therapeutic conditions did not cause histopathological abnormalities or alter serum biochemical parameters, indicating acceptable biocompatibility.
How does the synthesized Fm-COP exert its antitumor effects, and what is the evidence for apoptosis induction?
Fm-COPs disrupt the cytoskeleton, leading to inhibition of cell migration and invasion, and induce apoptosis. TUNEL staining in tumor sections from the G8 group showed significant apoptosis compared to controls, confirming the proapoptotic effect.
What is the tumor inhibition rate achieved by the dual-lock system, and how does it compare to conventional therapies?
The tumor inhibition rate in the G8 group exceeded 70%, significantly outperforming other groups. This efficacy is achieved without systemic toxicity, as evidenced by stable body weights and normal organ histology, suggesting a favorable therapeutic index compared to conventional chemotherapy.
What are the scalability and manufacturing challenges for translating this intracellular synthesis strategy to clinical use?
The strategy relies on small-molecule precursors and endogenous enzymes, which are scalable. However, ensuring consistent precursor stability, reproducible synthesis of Fm-COPs in vivo, and regulatory approval for the catalytic metal (Sc(OTf)3) are key challenges. The demonstrated biosafety and clearance profile support further development.
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