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Near-infrared boosted ROS responsive siRNA delivery and cancer therapy with sequentially peeled upconversion
Yuling He1, Shuwen Guo2, Lina Wu1
1State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023, China.
Abstract:
RNA interference (RNAi) therapy has become an appealing approach for cancer treatment, while the specificity and efficiency of controlled small interference RNA (siRNA) release remain challenging due to the heterogeneity of tumor environment. Herein, upconversion nano-onions (UCNOs) with stacked polymer coating layers are constructed to decompose sequentially in response to extracellular environment and NIR stimulation. The UCNOs (UCNPs-PEIRB-PEISeSe/siRNA-R8-HA) are composed of upconversion nanoparticles (UCNPs) core functionalized with inner coating layer of photosensitizer rose bengal (RB) conjugated PEI 600, middle coating layer of singlet oxygen (1O2) sensitive diselenide linked PEI 600 with therapeutic siRNA loading and cell-penetrating peptide R8 modification, and outer coating layer of negatively charged hyaluronic acid (HA). HA prevents siRNA leakage during delivery process and specifically targets tumor cells with overexpressed CD44 membrane receptors, and digested by cell secreted hyaluronidase (HAase). Upon the subsequent irradiation at 808 nm, UCNPs core generates emissions around 540 nm, which activate RB to boost ROS generation for complete PEI-SeSe decompose. The NIR boosted decompose of UCNOs induces a fast and efficient siRNA release, which effectively improves the gene silencing efficiency in vitro and suppresses tumor growth in vivo. The proposed sequentially responsive UCNOs have promising potential application in precision medicine.
Insights
This study introduces novel upconversion nano-onions (UCNOs) for targeted cancer therapy. These nanoparticles deliver small interfering RNA (siRNA) effectively by sequentially responding to the tumor environment and near-infrared (NIR) light, enhancing gene silencing and suppressing tumor growth.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Cancer Therapy
Background:
- RNA interference (RNAi) therapy shows promise for cancer treatment.
- Challenges exist in achieving specific and efficient small interfering RNA (siRNA) release due to tumor microenvironment heterogeneity.
Purpose of the Study:
- To develop upconversion nano-onions (UCNOs) for sequential, stimuli-responsive siRNA release.
- To enhance the specificity and efficiency of RNAi therapy for cancer treatment.
Main Methods:
- Constructed UCNOs with stacked polymer layers: upconversion nanoparticles (UCNPs) core, rose bengal (RB) and PEI 600 inner layer, diselenide-linked PEI 600 with siRNA and R8 peptide middle layer, and hyaluronic acid (HA) outer layer.
- Utilized NIR (808 nm) irradiation to activate UCNPs, generating emissions that activate RB, boosting ROS generation for polymer decomposition and siRNA release.
- Investigated HA targeting of CD44 receptors and HAase digestion for tumor cell specificity.
Main Results:
- UCNOs demonstrated sequential decomposition triggered by extracellular environment and NIR stimulation.
- NIR-boosted decomposition led to rapid and efficient siRNA release.
- Achieved improved in vitro gene silencing efficiency and significant in vivo tumor growth suppression.
Conclusions:
- Sequentially responsive UCNOs offer a promising platform for precise and efficient RNAi cancer therapy.
- The developed system effectively overcomes challenges associated with controlled siRNA release in heterogeneous tumor environments.
- UCNOs hold potential for applications in precision medicine.
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