The danger of persistently high uric acid extends far beyond the agonizing joint flares of gout. At the molecular level, excess urate activates the NLRP3 inflammasome, a cellular alarm complex that processes pro-inflammatory interleukins and triggers pyroptosis, an explosive form of cell death. Uric acid simultaneously engages NF-κB and MAPK signaling cascades, flooding tissues with reactive oxygen species. The consequences ripple through multiple organ systems: vascular endothelial cells lose nitric oxide and become dysfunctional, pancreatic beta cells undergo oxidative injury and apoptosis, and the kidneys accumulate fibrotic scarring. Epidemiological studies link hyperuricemia to hypertension, metabolic syndrome, insulin resistance, type 2 diabetes, renal dysfunction and cardiovascular disease, and proteomic analyses have revealed elevated complement proteins and altered HDL components in affected patients, deepening the picture of a truly systemic disorder.

Yet the therapeutic arsenal available today remains surprisingly limited. Xanthine oxidase inhibitors such as allopurinol and febuxostat, the first-line drugs, carry risks of severe skin reactions, particularly in carriers of the HLA-B*58:01 allele, along with hepatotoxicity and cardiac safety concerns for febuxostat. Allopurinol at standard doses fails to reach target urate levels in more than half of patients. Uricosuric agents like probenecid and benzbromarone are constrained by renal impairment, and the newer drug lesinurad carries a narrow therapeutic window with dose-dependent kidney toxicity. Even strict dietary restriction typically lowers serum urate by only about 1 mg/dL. Uricase biologics, which degrade uric acid into the more soluble allantoin, work powerfully but suffer from short circulating half-lives, high immunogenicity, and the awkward problem that their catalytic reaction produces hydrogen peroxide, a toxic byproduct.

The review organizes the newest wave of research into four progressive levels, beginning with the enzyme itself. Nanozyme-based cascade catalytic systems co-encapsulate uricase and catalase within a single nanocarrier, so that hydrogen peroxide generated during urate degradation is immediately decomposed into water and oxygen. One standout system wraps a dual-enzyme-loaded ZIF-8 metal-organic framework in a preformed albumin corona, cutting macrophage uptake by 73.4 percent and extending the drug’s half-life to 16.3 hours, 3.2 times that of free uricase. In chronically hyperuricemic mice, the formulation remained effective across six repeated injections while free uricase lost efficacy after the third. A related approach armors red blood cells with the same enzyme-loaded nanoparticles, exploiting the cells’ natural 120-day circulation time and CD47-mediated immune camouflage; the resulting biohybrids achieved an elimination half-life of 49.7 hours and normalized serum urate within two hours in mouse models.

Targeting is the next frontier. Because gout attacks draw massive neutrophil influx into affected joints, researchers coated uricase-catalase nanoparticles with neutrophil membranes, whose adhesion receptors home in on inflamed endothelium. Accumulation at gout sites rose roughly threefold compared with red-blood-cell-membrane controls, and a single intravenous dose normalized serum urate within two hours while outperforming colchicine at reducing joint swelling in crystal-induced arthritis models. Moving further from biology altogether, inorganic nanozymes replace fragile enzyme proteins with stable catalytic nanomaterials. Two-dimensional Pd@Ir nanosheets combine uricase-like and catalase-like activities in one structure, achieving an activation energy of just 35.9 kJ/mol at 46 nm, lower than natural bacterial uricase. Even more economically compelling is a manganese-based nanozyme derived from ZIF-8 that integrates three enzyme activities in a single non-noble-metal center, dissolves preformed monosodium urate crystals within 120 minutes, and relieves acute gout pain faster than colchicine in mouse models.

The second level of innovation concerns delivery. Hybrid cell membrane platforms fuse the targeting and immune-modulating properties of natural membranes with multimodal payloads: one system combining an M2 macrophage-exosome hybrid shell with uricase, a platinum nanozyme and resveratrol increased drug exposure 9.4-fold, reduced immunogenicity markers, and restored synovial tissue within 72 hours under near-infrared irradiation. Synthetic protocells offer a cell-free alternative. Artificial protocells built from polylysine-DNA coacervate droplets cloaked in PEGylated lipid membranes enriched enzymes thousands-fold, protected them from serum and trypsin, and accumulated in the kidneys at 5.7 to 7.7 times the level of free enzymes, reducing serum urate to 302 micromolar by day eleven in persistent hyperuricemia models. A hyaluronan-cloaked lipid vesicle system takes a different tack, engineering an internal alkaline microenvironment at pH 8.5 that preserves uricase activity and boosting relative bioavailability by roughly 533 percent.

The third and perhaps most provocative level shifts therapy from the bloodstream to the gut, which handles about one-third of human uric acid excretion. Oral delivery of enzymes has always been thwarted by stomach acid and digestive enzymes, but new systems are rewriting the rules. One hydrogel microsphere releases uricase in the intestine, where the hydrogen peroxide it generates reacts with endogenous catalase to drive dopamine polymerization that anchors the enzyme directly onto the intestinal mucosa. Serum urate fell by more than 70 percent, fecal urate excretion rose about 30 percent, and in an ex vivo test the immobilized enzyme reduced urate content in gout patients’ stool samples by 37 percent. Engineered probiotics go further still: a strain of Escherichia coli Nissle 1917 packages uricase into outer membrane vesicles that survive intestinal proteolysis and cross the gut barrier, cutting serum urate from 599.7 to 279.3 micromolar in mice and by 42.6 percent in preliminary human serum testing. A successor system called PULSE adds a uric-acid-responsive genetic circuit, expressing urate oxidase only when intestinal urate rises, maintaining serum urate below 300 micromolar for 30 days while avoiding dangerous over-depletion in healthy animals.

The fourth level moves beyond uricase entirely. Natural polysaccharides and oligosaccharides from plants such as Imperata cylindrica, Premna ligustroides and Coix seed act on multiple targets at once, inhibiting urate production, reshaping renal and intestinal urate transporters, suppressing the NLRP3 inflammasome and remodeling gut microbiota; one pectin preparation lowered serum urate by 59.32 percent, outperforming allopurinol’s 47.88 percent in the same mouse model. mRNA therapy attacks the evolutionary root of the problem: humans lost the uricase gene during primate evolution, and an ionizable lipid nanoparticle system delivering uricase mRNA restored urate-degrading capacity in mice for roughly two weeks after a single 0.5 mg/kg dose, successfully processing urate in 16 clinical patient serum samples ex vivo. Meanwhile, ImmTOR, rapamycin-loaded nanoparticles that induce antigen-specific immune tolerance, achieved direct clinical validation in a Phase 1 trial: patients co-administered with a pegylated uricase maintained serum urate below 6 mg/dL for 30 days with dose-dependent suppression of the anti-drug antibodies that normally destroy the therapy.

Formidable obstacles remain before any of this reaches routine clinical practice. Biologically derived materials such as cell membranes and plant polysaccharides vary batch to batch, complicating standardized manufacturing, while noble-metal nanozymes raise questions about long-term retention and cost. Engineered bacteria demand rigorous regulatory scrutiny of gene stability and horizontal transfer risk. Most preclinical evidence rests on chemically induced mouse models that poorly recapitulate human gout, and the hypoxic gut environment fundamentally limits oxygen-dependent uricase catalysis. The review’s authors also emphasize pharmacoeconomics: with cheap generic allopurinol entrenched as first-line therapy, novel nanotherapies will likely find their place not as universal replacements but in refractory gout, chronic kidney disease and other high-burden populations where current drugs fall short. Still, the trajectory is unmistakable, a coherent march from fixing a single enzyme toward rethinking urate metabolism across the whole body, and for the hundreds of millions living with rising uric acid, that march cannot come soon enough.

Subject of Research: Emerging nanomedicine, biomimetic delivery, gut-targeted and alternative therapeutic strategies for hyperuricemia

Article Title: Emerging therapeutic strategies for hyperuricemia: a comprehensive review of nanozymes, biomimetic delivery, gut-targeted systems, and alternative interventions

Article References: Lin, J., He, S., & Gao, X. (2026). Emerging therapeutic strategies for hyperuricemia: a comprehensive review of nanozymes, biomimetic delivery, gut-targeted systems, and alternative interventions. Results in Chemistry, 30, Article 103891. https://doi.org/10.1016/j.rechem.2026.103891

Image Credits: AI Generated

DOI: 10.1016/j.rechem.2026.103891

Keywords: hyperuricemia, gout, uric acid, nanozymes, uricase, metal-organic frameworks, biomimetic delivery, engineered probiotics, mRNA therapy, immune tolerance, gut microbiota, nanomedicine