The glycosaminoglycan hyaluronan (HA) is an essential and ubiquitous component of human tissues and biofluids. The only known covalent modification of HA entails the attachment of heavy chains (HC) from the inter-alpha-inhibitor (IαI) family of proteoglycans, forming stable complexes (HC•HA) that arise during inflammation. In some contexts, HC•HA is thought to contribute to pathology, whereas in others it may form part of a protective pathway. However, its exact roles are not fully understood. Here, we report that HC modifications can protect HA from fragmentation by reactive oxygen species (ROS) produced during the inflammatory cascade. Using solid-state nanopore molecular size analysis, we show that HA is highly resistant to degradation from exogenous ROS in vitro when in the context of HC•HA complexes, while the unmodified HA polymer is fragmented rapidly under the same conditions. Experiments performed with admixtures of HA and unbound antioxidant proteins – including HC-bearing components – demonstrate the necessity of covalent HC attachment to the polysaccharide for the protection. Finally, we find that HA with high-HC content from ‘inflammatory’ equine synovial fluid has increased resilience to ROS damage compared to low-HC HA from a healthy joint. Collectively, these results demonstrate that covalent HC modification is an effective biological strategy for preserving HA integrity against ROS fragmentation, including in inflammatory conditions. ### Competing Interest Statement ARH and PLD are listed as inventors on a patent covering the nanopore size analysis approach. All other authors declare no competing interests. National Institutes of Health, 5R01GM134226-06, P41EB020594 Arthritis Research UK, 22277 Wellcome Trust, 203128/Z/16/Z, 220926/Z/20/Z, 304200/Z/23/Z

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