Wednesday, April 2, 2025
4/2/2025
Exploring nano-bio interactions for cell-specific targeting of osteoarthritis - Exploring nano-bio interactions for cell-specific targeting in osteoarthritis In the US, osteoarthritis (OA) is the most prevalent chronic joint disease. However, there is still no FDA-approved disease-modifying therapy for this disease. Nanoparticle (NP)-mediated delivery of RNA is emerging as a promising approach for treating OA. However, OA, as a whole joint disease, is marked by the pathological alterations of multiple joint tissues and cells. Thus, one single treatment may not be able address all these changes, necessitating tissue and cell-specific targeting. Off-target delivery of therapeutics will not only diminish the efficiency, but also lead to counter-productive effects. Yet, to date, no NPs have the capacity to achieve cell- specific targeting in the joint, constituting a critical need for precision NPs that can enable effective OA therapy. Through variations of size and chemical composition, thousands of NPs can be formulated to have different affinities to different cell types. Individually testing these NPs to select the best formulation for each cell type is extremely inefficient. But there has not been an efficient screening method to address the critical need of cell- specific targeting. We propose a transformative high throughput approach to screen for NPs targeting specific OA joint cells. We named it JOINTseq, for Joint Nanoparticle Targeting with single cell RNAseq. Each uniquely formulated NP will be loaded with a matching DNA barcode. A cocktail of them will constitute a library of NPs for intraarticular injection into the mouse joint. By performing scRNAseq, we will capture cellular mRNAs of each cell as well as the DNA barcodes of the NPs that enter this cell. As such, specific NPs that target individual cell types can be identified. In our preliminary study, we have observed clear preferences of different variations of poly-(lactic-co-glycolic acid) (PLGA) NPs for several joint cell types in vitro. When NPs were injected into the mice, their DNA barcodes were readily identified, providing strong feasibility for barcoding NPs. Our central hypothesis is that JOINTseq can screen NPs with unique structural and functional properties for precise, cell-specific delivery of therapeutics in the OA joint environment. To test this hypothesis, we will screen a library of DNA-barcoded NPs using JOINTseq to identify NPs that can target specific cell types in OA joints. Next, we will demonstrate the utility of selected NPs to deliver mRNA into mouse OA joints and human OA tissues in cell-specific manner. Success from this study will lead to a new screening method for identifying NPs for cell-specific targeting and provide critical insights into the nano-bio interaction at a cellular level. Thus, this work will enable us to embark on a new era of precision NP design for OA therapy. With the increasing awareness of heterogeneity in all cell types, this approach will open a new horizon for precision gene therapy at unprecedented resolution and has a transformative impact on OA therapy.
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