Project Portugal 2030

Summary

Current OA treatments promote symptomatic relief without controlling the biological processes underlying tissue damage. To regulate and resolve OA complications, inHALE aims to fabricate the next generation of OA modifying agents in the form of respirable dry powders. This ambitious goal will be accomplished by: i) Design of precision nanocomplexes. The delivery of OA-modifying miRNA will be performed by nanocomplexes formed by electrostatic interactions between natural-origin polymers (e.g. hyaluronic acid, chondroitin sulfate) and miRNA. Nanocomplexes are envisioned to stabilize and deliver the miRNA ensuring their bioactivity and physical stability during production and shelf-life. Verification: Nanoplexes produced with adequate physico-chemical properties, dimensions, and structural integrity of miRNA will be an indicator of the successful fabrication of these particles. ii) Rendering nanoplexes with improved biorecognition and homing moieties. Following a bioinspired approach, nanoplexes will be linked to segments of macrophage membranes forming biomimetic nanoplexes (BioNPs). Macrophages are naturally responsive to inflamed or injured tissues thus, elements of macrophage membrane will reinforce systemic navigation of nanoplexes to the OA joints and enhance their therapeutic efficacy. Biomimetic camouflage avoids artificial modifications with poor biorecognition as well as PEGylation risks, such as immune stimulation, cytoplasmic vacuolation, or hypersensitivity reactions (Shi et al., 2022). Verification: Biological assays will determine the interactions of BioNPs with blood using chips, and with cells using lung barrier- and inflammatory- models. iii) Fabrication of respirable OA modifying powders. The success of inhalable therapy as a main-stream treatment for OA requires a suitable and up-scalable manufacturing process compatible with miRNA. Nanosuspensions of BioNPs will be combined with dissolved bulking or shell-forming agents and converted to powders by spray drying for improved dispersibility in the airways foreseeing their use in conventional inhaler devices. Verification: The production of dry powder formulations with adequate aerodynamic dimensions, and muco-resistant cues. iv) Respirable OA-modifying powders with biological functionality. The major challenge after the fabrication of inhalable powders is to promote remote reprograming of cell fate stimulating appropriate phenotypes to control inflammation and matrix degradation. Verification. Inhalable dry powders will be assessed for cell viability, and inflammatory profiles in cell and mice models to confirm their applicability as OA-modifying therapeutics. inHALE is cross-disciplinary. To achieve these goals, inHALE merges biology and RNA-based technology to shape the expression of molecular triggers responsible for inflammatory pain and tissue degradation with biomaterials sciences and particle fabrication employing green and up-scalable processes compatible with physiological conditions to assure miRNA activity. Aiming at producing novel therapy solutions, inHALE meets medical sciences as well as pharma sciences proposing the next generation of inhalable medicines for OA and resourcing to spray drying, a method widely employed to produce antibiotic powders and particles with controlled properties. Thus, inHALE fosters innovation and creativity from different scientific perspectives to accomplish a holistic resolution for the clinical management of OA.