Rational design for controlled release of Dicer-substrate siRNA harbored in phi29 pRNA-based nanoparticles.

Small interfering RNA (siRNA) for silencing genes and treating disease has been a dream since ranking as a top Breakthrough of the Year in 2002 by . With the recent FDA approval of four siRNA-based drugs, the potential of RNA therapeutics to become the third milestone in pharmaceutical drug development has become a reality. However, the field of RNA interference (RNAi) therapeutics still faces challenges such as specificity in targeting, intracellular processing, and endosome trapping after targeted delivery.

3D RNA nanocage for encapsulation and shielding of hydrophobic biomolecules to improve the biodistribution.

Ribonucleic acid (RNA) nanotechnology platforms have the potential of harboring therapeutics for delivery in disease treatment. However, the nonspecific interaction between the harbored hydrophobic drugs and cells or other components before reaching the diseased site has been an obstacle in drug delivery. Here we report an encapsulation strategy to prevent such nonspecific hydrophobic interactions and based on a self-assembled three-dimensional (3D) RNA nanocage.

Ultra-thermostable RNA nanoparticles for solubilizing and high-yield loading of paclitaxel for breast cancer therapy.

Paclitaxel is widely used in cancer treatments, but poor water-solubility and toxicity raise serious concerns. Here we report an RNA four-way junction nanoparticle with ultra-thermodynamic stability to solubilize and load paclitaxel for targeted cancer therapy. Each RNA nanoparticle covalently loads twenty-four paclitaxel molecules as a prodrug.

RNA Nanotechnology to Solubilize Hydrophobic Antitumor Drug for Targeted Delivery.

Small-molecule drugs are used extensively in clinics for cancer treatment; however, many antitumor chemical drugs dissolve poorly in aqueous solution. Their poor solubility and nonselective delivery in vivo often cause severe side effects. Here, the application of RNA nanotechnology to enhance the solubility of hydrophobic drugs, using camptothecin (CPT) for proof-of-concept in targeted delivery for cancer treatment is reported.

Tuning the size, shape and structure of RNA nanoparticles for favorable cancer targeting and immunostimulation.

The past decade has shown exponential growth in the field of RNA nanotechnology. The rapid advances of using RNA nanoparticles for biomedical applications, especially targeted cancer therapy, suggest its potential as a new generation of drug. After the first milestone of small molecule drugs and the second milestone of antibody drugs, it was predicted that RNA drugs, either RNA itself or chemicals/ligands that target RNA, will be the third milestone in drug development.

Photo-controlled release of paclitaxel and model drugs from RNA pyramids.

Stimuli-responsive release of drugs from a nanocarrier in spatial-, temporal-, and dosage-controlled fashions is of great interest in the pharmaceutical industry. Paclitaxel is one of the most effective and popular chemotherapeutic drugs against a number of cancers such as metastatic or nonmetastatic breast cancer, non-small cell lung cancer, refractory ovarian cancer, AIDS-related Kaposi's sarcoma, and head and neck cancers. Here, by taking the advantage of RNA nanotechnology in biomedical and material science, we developed a three-dimensional pyramid-shaped RNA nanocage for a photocontrolled release of cargo, using paclitaxel as a model drug.

Delivery of Anti-miRNA for Triple-Negative Breast Cancer Therapy Using RNA Nanoparticles Targeting Stem Cell Marker CD133.

Triple-negative breast cancer (TNBC) is an aggressive disease with a short median time from relapse to death. The increased aggressiveness, drug resistance, disease relapse, and metastasis are associated with the presence of stem cells within tumors. Several stem cell markers, such as CD24, CD44, CD133, ALDH1, and ABCG2, have been reported, but their roles in breast cancer tumorigenesis remain unclear.

RNA Micelles for the Systemic Delivery of Anti-miRNA for Cancer Targeting and Inhibition without Ligand.

Displaying the advantage of nanoparticles in cancer targeting and drug delivery, micelles have shown great potential in cancer therapy. The mechanism for micelle targeting to cancer without the need for ligands is due to the size advantage of micelles within the lower end of the nanometer scale that is the optimal size for favoring the enhanced permeability and retention (EPR) effect while escaping trapping by macrophages. MicroRNAs are ubiquitous and play critical roles in regulating gene expression, cell growth, and cancer development.

Arrowtail RNA for Ligand Display on Ginger Exosome-like Nanovesicles to Systemic Deliver siRNA for Cancer Suppression.

Exosomes have shown increasing potential as delivery vesicles for therapy, but challenges like cost/yield, drug payload, and targeting specificity still exist. Plant derived exosome-like nanoparticles have been reported as a promising substitution and exhibit biocompatibility through oral, intranasal administration; however, systemic delivery of siRNA by exosome-like nanoparticles directly isolated from plants has not been reported. Recently, we reported the control of RNA orientation to decorate human derived exosome with cell targeting ligands for specific delivery of siRNA to tumors.

RNA-based micelles: A novel platform for paclitaxel loading and delivery.

RNA can serve as powerful building blocks for bottom-up fabrication of nanostructures for biotechnological and biomedical applications. In addition to current self-assembly strategies utilizing base pairing, motif piling and tertiary interactions, we reported for the first time the formation of RNA based micellar nanoconstruct with a cholesterol molecule conjugated onto one helical end of a branched pRNA three-way junction (3WJ) motif. The resulting amphiphilic RNA micelles consist of a hydrophilic RNA head and a covalently linked hydrophobic lipid tail that can spontaneously assemble in aqueous solution via hydrophobic interaction.

Hydrophobic Effect from Conjugated Chemicals or Drugs on In Vivo Biodistribution of RNA Nanoparticles.

Liver or other organ accumulation of drugs is one of the major problems that leads to toxicity and side effects in therapy using chemicals or other macromolecules. It has been shown that specially designed RNA nanoparticles can specifically target cancer cells, silence oncogenic genes, and stop cancer growth with little or no accumulation in the liver or other vital organs. It is well known that physical properties of nanoparticles such as size, shape, and surface chemistry affect biodistribution and pharmacokinetic profiles in vivo.