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Macrophage Membrane-Cloaked, ROS-Triggered Quercetin Nanocarriers Target Ovarian Lesions to Treat Polycystic Ovary
Wenzhu Li1, Yu Guan1, Nan Song2
1Reproductive Medicine Center, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, China.
Abstract:
Polycystic ovary syndrome (PCOS) involves oxidative stress-driven ovarian dysfunction and remains difficult to treat due to drug side effects and poor target engagement. We engineered a reactive oxygen species (ROS)-responsive, macrophage-membrane-camouflaged quercetin nano-therapy (MM@PCD@QNPs) to enhance ovarian delivery and mitigate toxicity. The core comprises a pinacol phenylboronate-dextran conjugate that encapsulates quercetin and undergoes ROS-triggered release; a surface M0 macrophage membrane confers immune evasion and lesion tropism via retained proteins (e.g., CD11b and CD47-SIRPα). MM@PCD@QNPs displayed nanoscale dimensions and stability (133.63 ± 14.60 nm; -33.13 ± 1.52 mV) and released drug under elevated ROS. In DHT-injured granulosa cells and a DHEA-induced PCOS mouse model, the formulation promoted granulosa cell proliferation, suppressed apoptosis, reduced ROS, and preferentially accumulated in ovaries, with negligible in vitro and in vivo toxicity. Transcriptomics and validation implicate activation of the MAPK7-Nrf2-NQO1 axis as a principal mechanism; pharmacologic MAPK7 inhibition abrogated therapeutic effects. By coupling ROS-triggered release with macrophage-mimetic targeting, MM@PCD@QNPs overcome quercetin's low bioavailability and off-target exposure and provide a safe, effective nanoplatform for PCOS therapy.
Insights
A novel nanoparticle therapy using quercetin, designed to target ovarian dysfunction in polycystic ovary syndrome (PCOS), effectively reduces oxidative stress and improves cell function with minimal toxicity.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Reproductive Endocrinology
Background:
- Polycystic ovary syndrome (PCOS) is characterized by oxidative stress-induced ovarian dysfunction, posing treatment challenges due to drug toxicity and poor targeting.
- Current therapeutic strategies for PCOS often suffer from side effects and limited efficacy in reaching the target ovarian tissues.
Purpose of the Study:
- To develop and evaluate a novel reactive oxygen species (ROS)-responsive nanoparticle system for targeted quercetin delivery to the ovaries in PCOS.
- To enhance the therapeutic efficacy of quercetin by improving its bioavailability and reducing off-target toxicity in PCOS treatment.
Main Methods:
- Engineered macrophage-membrane-camouflaged quercetin nanoparticles (MM@PCD@QNPs) with ROS-triggered release capabilities.
- Evaluated nanoparticle characteristics (size, stability, drug release) and therapeutic effects in DHT-injured granulosa cells and a DHEA-induced PCOS mouse model.
- Investigated the underlying therapeutic mechanisms using transcriptomics and pharmacologic inhibition of key signaling pathways.
Main Results:
- MM@PCD@QNPs demonstrated nanoscale dimensions, stability, and ROS-triggered quercetin release.
- The formulation effectively promoted granulosa cell proliferation, reduced apoptosis and ROS levels, and preferentially accumulated in ovaries in a PCOS mouse model.
- Negligible in vitro and in vivo toxicity was observed, indicating a favorable safety profile.
Conclusions:
- MM@PCD@QNPs represent a safe and effective nanoplatform for PCOS therapy by overcoming quercetin's limitations.
- The therapy functions by activating the MAPK7-Nrf2-NQO1 signaling axis, offering a targeted approach to mitigating ovarian dysfunction in PCOS.
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