A pH-responsive metal-organic framework for the co-delivery of HIF-2α siRNA and curcumin for enhanced therapy of osteoarthritis

Abstract

The occurrence of osteoarthritis (OA) is highly correlated with the reduction of joint lubrication performance, in which persistent excessive inflammation and irreversible destruction of cartilage dominate the mechanism. The inadequate response to monotherapy methods, suboptimal efficacy caused by undesirable bioavailability, short retention, and lack of stimulus-responsiveness, are few unresolved issues. Herein, we report a pH-responsive metal-organic framework (MOF), namely, MIL-101-NH2, for the co-delivery of anti-inflammatory drug curcumin (CCM) and small interfering RNA (siRNA) for hypoxia inducible factor (HIF-2α). CCM and siRNA were loaded via encapsulation and surface coordination ability of MIL-101-NH2. Our vitro tests showed that MIL-101-NH2 protected siRNA from nuclease degradation by lysosomal escape. The pH-responsive MIL-101-NH2 gradually collapsed in an acidic OA microenvironment to release the CCM payloads to down-regulate the level of pro-inflammatory cytokines, and to release the siRNA payloads to cleave the target HIF-2α mRNA for gene-silencing therapy, ultimately exhibiting the synergetic therapeutic efficacy by silencing HIF-2α genes accompanied by inhibiting the inflammation response and cartilage degeneration of OA. The hybrid material reported herein exhibited promising potential performance for OA therapy as supported by both in vitro and in vivo studies and may offer an efficacious therapeutic strategy for OA utilizing MOFs as host materials.

Recent advances in metal–organic frameworks for stimuli-responsive drug delivery

“…19 Schematic representation of pH-responsive MOFs for osteoarthritis. 430 ery systems based on stimuli-responsive MOFs, some problems remain unsolved. There is currently a lack of systematic and comprehensive naming standard to uniformly name complex MOFs.…”

“…The in vivo results demonstrated that compared with the destruction of cartilage tissue in groups of blank control and PCA, newly formed glossy and smooth cartilage-like tissues were observed in the MOF@HA@PCA group. Zhang et al fabricated pH-responsive MIL-101-NH 2 nanoparticles loaded with curcumin (CCM) and small interfering RNA (siRNA) for hypoxia-inducible factor (HIF-2α), denoted as MCS NPs, for OA treatment 430 (Fig. 19).…”

Recent developments of polymeric delivery systems in gene therapeutics

“…151 Compared with normal cartilage, the expression of hypoxia-inducible factor 2α (HIF-2α) is significantly increased in articular chondrocytes of osteoarthritis (OA) patients, which induces calcification as well as apoptosis of hypertrophic chondrocytes around the perichondral bone, leading to cartilage matrix degradation. 152 Constructing a suitable gene vector to silence the HIF2α gene in articular chondrocytes will be the key to alleviating articular cartilage degeneration and treating OA. However, articular cartilage itself has no blood vessels, nerve tissue, and lymphatic distribution, and the extracellular matrix of chondrocytes is dense (pore size of about 60 nm) and has a negative electrical barrier, making it difficult to deliver drugs/genes to chondrocytes.…”

Surface functionalization of metal–organic framework nanoparticle for overcoming biological barrier in cancer therapy

“…3C). 61 The loading of both CCM and siRNA onto MIL-101-NH 2 was accomplished through a combination of encapsulation mechanisms and the surface coordination capabilities inherent to MIL-101-NH 2 . These in vitro experiments revealed that MIL-101-NH 2 exhibits a pronounced protective effect against siRNA, shielding it from nuclease degradation via lysosomal escape.…”