Intravesical delivery of KDM6A -mRNA via mucoadhesive nanoparticles inhibits the metastasis of bladder cancer

Abstract

Lysine-specific demethylase 6A (KDM6A), also named UTX, is frequently mutated in bladder cancer (BCa). Although known as a tumor suppressor, KDM6A’s therapeutic potential in the metastasis of BCa remains elusive. It also remains difficult to fulfill the effective up-regulation of KDM6A levels in bladder tumor tissues in situ to verify its potential in treating BCa metastasis. Here, we report a mucoadhesive messenger RNA (mRNA) nanoparticle (NP) strategy for the intravesical delivery of KDM6A-mRNA in mice bearing orthotopic Kdm6a-null BCa and show evidence of KDM6A’s therapeutic potential in inhibiting the metastasis of BCa. Through this mucoadhesive mRNA NP strategy, the exposure of KDM6A-mRNA to the in situ BCa tumors can be greatly prolonged for effective expression, and the penetration can be also enhanced by adhering to the bladder for sustained delivery. This mRNA NP strategy is also demonstrated to be effective for combination cancer therapy with other clinically approved drugs (e.g., elemene), which could further enhance therapeutic outcomes. Our findings not only report intravesical delivery of mRNA via a mucoadhesive mRNA NP strategy but also provide the proof-of-concept for the usefulness of these mRNA NPs as tools in both mechanistic understanding and translational study of bladder-related diseases.

Layered double hydroxide-based nanomaterials for biomedical applications

“…Gene therapy is a promising treatment for gene-related diseases (e.g., cancers, neurodegenerative disorders and some infectious diseases), which refers to the use of negatively charged nucleic acid molecules with therapeutic functions, such as DNA, siRNA, short hairpin RNA (shRNA) and microRNA (miRNA). 65,[253][254][255][256] Unfortunately, the low delivery efficiency, easy degradability, high toxicity and poor anticancer specificity of nucleic acids hinder their clinical application. 257 With a view to overcome these limitations, many studies have been carried out utilizing LDHs as biodegradable gene delivery vectors since the 2000s.…”

Emerging mRNA technologies: delivery strategies and biomedical applications

“…Hybrid carriers containing both lipid and polymer exhibit the advantages of both. 10 Decoration of mRNA-loaded polymeric NPs with lipid could further enhance their stability and pharmacokinetics by prolonging the circulation time after intravenous injection, through evading uptake by the reticuloendothelial system. In addition, mRNA delivery systems formed by organic/inorganic hybrid NPs, such as metal-organic framework (MOF), gold nanoparticles, and graphene oxide-PEI complexes are also addressed below.…”

“…Consequently, various materials have previously been employed for mRNA delivery, including lipids, 6 lipid-like materials, 7 polymers, 8 inorganic materials, 9 cell membranes, and hybrid systems. 10 Among them, lipids and lipid-like materials containing a polar head group, a hydrophobic chain, and a linker are the most commonly used. They interact with the negatively charged mRNA through electrostatic interactions to ensure the functional integrity of mRNA and facilitate its endosomal escape.…”

Minimally invasive nanomedicine: nanotechnology in photo-/ultrasound-/radiation-/magnetism-mediated therapy and imaging

“…1 In this review, we provide a comprehensive review of the research status of MINs in therapy and imaging, while the mechanisms of the corresponding MIT are also discussed. Additionally, the applications of MINs in various biomedical fields including cancers, [27][28][29] cardiovascular diseases, 30,31 tissue engineering, [32][33][34][35] neurofunctional diseases, 36,37 and infectious diseases, 38,39 and their combination with other treatment modes are summarized (Scheme 1). Finally, we share our thoughts regarding the challenges, future development, and clinical translation of MINs.…”