Akk, A. | Search bioRxiv

bioRxiv2026

Adipose-driven complement-lipid reprogramming controls nociceptive vulnerability in obesity-associated osteoarthritis

Obesity amplifies osteoarthritis (OA) pain disproportionately to joint damage, creating a major unmet clinical need for non-opioid interventions that act beyond the joint. Using OA as a translational model, we integrated serum multi-omics in obese mice with surgically induced OA and genetic and adipose-reconstitution models of complement factor D (FD). In humans, we analyzed longitudinal metabolomics data from the IDEA weight-loss trial and conducted functional studies in dorsal root ganglion (DRG) neurons. Adipose-derived FD emerged as a regulator of systemic immunometabolic state: FD deficiency in obese mice worsened pain sensitivity whereas restoring circulating FD normalized pain and inflammatory markers without altering joint structure. Cross-species lipid profiling identified conserved shifts in linoleic acid versus arachidonic acid-derived lipids that were associated with pain phenotypes in mice and with pain improvement in humans. Defined lipid cocktails modulated excitability and TRPV1 sensitivity in human DRG neurons, and transcriptomics of knee-innervating DRGs revealed diet and FD-dependent activation of complement and neuronal excitability pathways. Together, these findings define an adipose-complement-lipid axis that regulates nociceptive vulnerability independent of joint damage and identify extra-articular targets for translational, non-opioid OA pain therapies. One Sentence SummaryWe identify an adipose-complement-lipid axis that systemically regulates sensory neuron sensitization, providing a mechanistic basis for pain-structure discordance in obesity-associated osteoarthritis.

physiology↗

bioRxiv2024

Systemic delivery of murine SOD2 mRNA to experimental abdominal aortic aneurysm mitigates expansion and rupture

BackgroundOxidative stress is implicated in the pathogenesis and progression of abdominal aortic aneurysm (AAA). Antioxidant delivery as a therapeutic for AAA is of substantial interest although clinical translation of antioxidant therapy has met with significant challenges due to limitations in achieving sufficient antioxidant levels at the site of AAA. We posit that nanoparticle-based approaches hold promise to overcome challenges associated with systemic administration of antioxidants. MethodsWe employed a peptide-based nanoplatform to overexpress a key modulator of oxidative stress, superoxide dismutase 2 (SOD2). The efficacy of systemic delivery of SOD2 mRNA as a nanotherapeutic agent was studied in two different murine AAA models. Unbiased mass spectrometry-enabled proteomics and high-dimensional bioinformatics were used to examine pathways modulated by SOD2 overexpression. ResultsThe murine SOD2 mRNA sequence was mixed with p5RHH, an amphipathic peptide capable of delivering nucleic acids in vivo to form self-assembled nanoparticles of [~]55 nm in diameter. We further demonstrated that the nanoparticle was stable and functional up to four weeks following self-assembly when coated with hyaluronic acid. Delivery of SOD2 mRNA mitigated the expansion of small AAA and largely prevented rupture. Mitigation of AAA was accompanied by enhanced SOD2 protein expression in aortic wall tissue. Concomitant suppression of nitric oxide, inducible nitric oxide synthase expression, and cell death was observed. Proteomic profiling of AAA tissues suggests that SOD2 overexpression augments levels of microRNAs that regulate vascular inflammation and cell apoptosis, inhibits platelet activation/aggregation, and downregulates mitogen-activated protein kinase signaling. Gene set enrichment analysis shows that SOD2 mRNA delivery is associated with activation of oxidative phosphorylation, lipid metabolism, respiratory electron transportation, and tricarboxylic acid cycle pathways. ConclusionsThese results confirm that SOD2 is key modulator of oxidative stress in AAA. This nanotherapeutic mRNA delivery approach may find translational application in the medical management of small AAA and the prevention of AAA rupture.

cell biology↗