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Engineered extracellular vesicles for combinatorial TNBC therapy: SR-SIM-guided design achieves substantial drug
Abhjeet S Bhullar1, Kai Jin2, Haizhu Shi3
1Center for RNA Nanobiotechnology and Nanomedicine, College of Pharmacy and Comprehensive Cancer Center. The Ohio State University, Columbus, OH 43210, USA; Interdisciplinary Biophysics Graduate Program, The Ohio State University, Columbus, OH 43210, USA.
Abstract:
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that has no therapeutic targets, relies on chemotherapeutics for treatment, and is in dire need of novel therapeutic approaches for improved patient outcomes. Extracellular vesicles (EVs) serve as intercellular communicators and have been proposed as ideal drug delivery vehicles. Here, EVs were engineered with RNA nanotechnology to develop TNBC tumor inhibitors. Using super resolved-structured illumination microscopy, EVs were optimized for precise Survivin small interfering RNA (siRNA) conjugated to chemotherapeutics loading and CD44 aptamer ligand decoration, thereby enhancing specificity toward TNBC cells. Conventional treatments typically employ chemotherapy drugs gemcitabine (GEM) and paclitaxel (PTX) at dosages on the order of mg/kg respectively, per injection (intravenous) in mice. In contrast, engineered EVs encapsulating these drugs saw functional tumor growth inhibition at significantly reduced concentrations: 2.2 μg/kg for GEM or 5.6 μg/kg for PTX, in combination with 21.5 μg/kg survivin-siRNA in mice. The result is a substantial decrease in the chemotherapeutic dose required, by orders of magnitude, compared with standard regimens. In vivo and in vitro evaluations in a TNBC orthotopic xenograft mouse model demonstrated the efficacy of this decreased dosage strategy, indicating the potential for decreased chemotherapy-associated toxicity.
Insights
Engineered extracellular vesicles deliver chemotherapy and survivin siRNA to triple-negative breast cancer cells, significantly reducing drug dosage and toxicity. This novel approach shows promise for more effective TNBC treatment.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Oncology
Background:
- Triple-negative breast cancer (TNBC) lacks targeted therapies, necessitating improved treatment strategies.
- Extracellular vesicles (EVs) are promising natural nanocarriers for drug delivery.
- RNA nanotechnology offers precise engineering of EVs for targeted cancer therapy.
Purpose of the Study:
- To engineer EVs using RNA nanotechnology for targeted delivery of therapeutic agents to TNBC.
- To enhance EV specificity towards TNBC cells using CD44 aptamer decoration.
- To evaluate the efficacy of engineered EVs in reducing chemotherapeutic dosage and associated toxicity.
Main Methods:
- EVs were engineered with survivin small interfering RNA (siRNA) and chemotherapeutics (gemcitabine and paclitaxel).
- CD44 aptamer ligands were conjugated to EVs for enhanced TNBC cell targeting.
- Super-resolved structured illumination microscopy was used for EV optimization.
- In vivo and in vitro studies were conducted using a TNBC orthotopic xenograft mouse model.
Main Results:
- Engineered EVs achieved functional tumor growth inhibition at significantly reduced gemcitabine (2.2 μg/kg) and paclitaxel (5.6 μg/kg) concentrations compared to conventional methods.
- The combination therapy included 21.5 μg/kg survivin-siRNA.
- A substantial, orders-of-magnitude decrease in required chemotherapeutic dose was observed.
- Demonstrated efficacy in reducing chemotherapy-associated toxicity.
Conclusions:
- Engineered EVs loaded with chemotherapeutics and survivin-siRNA represent a potent strategy for TNBC treatment.
- This approach significantly lowers effective drug concentrations, potentially minimizing side effects.
- Targeted EV delivery holds promise for improving patient outcomes in aggressive TNBC.
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