Cell-Selective Delivery of RIBOTACs via an Anti-EGFR Nanobody for Pancreatic Cancer Treatment
Tianli Luo1,2, Yijuan Wang1, Dengwang Chen3
1Department of Surgery, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China.
Abstract:
Pancreatic ductal adenocarcinoma (PDAC) remains a therapeutic challenge due to its dense stroma and lack of druggable targets. Through integrated bioinformatics analysis of in-house and public datasets, we systematically identified miR-21 as the most significantly upregulated oncomiR in PDAC, showing strong correlation with poor patient prognosis. RNA-targeted degradation has emerged as a promising strategy for cancer treatment, enabling precise disruption of oncogenic signaling by degrading disease-driving non-coding RNAs. Nevertheless, poor tissue penetration and insufficient tumor specificity limit its therapeutic potential in pancreatic cancer, owing to the dense fibrotic stroma and heterogeneous target expression. Herein, we developed a dual-targeting, bioresponsive Nb-RIBOTAC (Nb-Fc-Val-Cit-RIBOTAC), engineered by conjugating a cathepsin B-responsive linker to bridge an EGFR-targeting nanobody (Nb-Fc fusion) with a miR-21-specific RIBOTAC module. This rationally designed therapeutic achieved potent and selective miR-21 degradation in orthotopic PDAC models, with 60% target knockdown while completely sparing normal tissues, leading to significant tumor growth inhibition. Our study establishes a transformative paradigm bridging bioinformatic identification with precision RNA degradation technology, offering new therapeutic possibilities for PDAC treatment. The target selection strategy and modular design principles described herein may be broadly applicable to other challenging malignancies.
Insights
Researchers identified miR-21 as a key driver in pancreatic cancer (PDAC). They developed a novel RNA degradation therapy that selectively targets and degrades miR-21 in tumors, significantly inhibiting growth and offering new treatment possibilities.
Area of Science:
- Oncology
- Molecular Biology
- Biotechnology
Background:
- Pancreatic ductal adenocarcinoma (PDAC) presents significant therapeutic challenges due to its dense stroma and limited druggable targets.
- MicroRNA-21 (miR-21) is a crucial oncomiR significantly upregulated in PDAC, correlating with poor patient prognosis.
- Current RNA-targeted degradation therapies face limitations in tissue penetration and tumor specificity for PDAC treatment.
Purpose of the Study:
- To identify key molecular targets driving PDAC progression through integrated bioinformatics analysis.
- To develop an advanced RNA degradation therapeutic with enhanced tissue penetration and tumor specificity for PDAC.
- To evaluate the efficacy of the novel therapeutic in inhibiting PDAC growth in preclinical models.
Main Methods:
- Integrated bioinformatics analysis of PDAC datasets to identify significant oncomiRs.
- Engineering of a dual-targeting, bioresponsive Nb-RIBOTAC system by conjugating an EGFR-targeting nanobody with a miR-21-specific RIBOTAC module via a cathepsin B-cleavable linker.
- Assessment of therapeutic efficacy, including target knockdown, tissue specificity, and tumor growth inhibition, in orthotopic PDAC models.
Main Results:
- Systematic identification of miR-21 as the most significantly upregulated oncomiR in PDAC, strongly associated with poor prognosis.
- Development of a rationally designed Nb-Fc-Val-Cit-RIBOTAC therapeutic achieving potent and selective miR-21 degradation in orthotopic PDAC models.
- Demonstration of significant tumor growth inhibition with approximately 60% miR-21 knockdown in tumors while sparing normal tissues.
Conclusions:
- The study establishes a novel therapeutic paradigm for PDAC by combining bioinformatic target identification with precision RNA degradation technology.
- The developed dual-targeting, bioresponsive Nb-RIBOTAC demonstrates significant potential for treating PDAC by selectively degrading oncogenic miR-21.
- The modular design and target selection strategy may offer broad applicability for treating other challenging malignancies.
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