Cyclodextrin‐based delivery of Annexin A1 mimetic Ac2–26 enhances anti‐inflammatory effect and prevents dengue‐induced lethality combined with antiviral therapy

Abstract Background and Purpose Severe dengue is characterised by systemic inflammation, cytokine storm, vascular leakage and haemorrhagic manifestations, largely driven by the host immune response to dengue virus (DENV) infection. Despite its burden, no licensed antivirals or host‐directed therapies are currently available. Our group has previously identified Annexin A1 (AnxA1) as an endogenous regulator of inflammation in dengue. Treatment with the AnxA1 peptidomimetic, Ac 2–26 , improved clinical outcomes in murine models of severe dengue by promoting resolution of inflammation without affecting viral control. Experimental Approach To explore new delivery strategies, we developed a novel formulation of Ac 2–26 complexed with hydroxypropyl‐β‐cyclodextrin (CDX‐Ac 2–26 ). Key Results In DENV‐2‐infected A129 mice, both intraperitoneal and oral CDX‐Ac 2–26 improved clinical scores and reversed thrombocytopenia. Notably, CDX‐Ac 2–26 reduced mast cell degranulation, MCPT‐1 plasma levels and CCL2 expression in spleen, with no effect on viral titres, indicating a host‐targeted mechanism and overcoming the anti‐inflammatory effects of the free peptide. Intraperitoneal administration achieved the same efficacy as oral dosing with only one‐third of the dose. Importantly, the combination of CDX‐Ac 2–26 with the antiviral nucleotide analogue sofosbuvir fully prevented disease and mortality in infected mice, highlighting a combinatorial effect between host‐directed and antiviral therapies. Conclusion and Implications These findings underscore the therapeutic potential of anti‐inflammatory/pro‐resolving strategies in severe dengue and support the development of CDX‐Ac 2–26 as a novel adjunctive treatment. Combining anti‐inflammatory and antiviral approaches may enhance efficacy and reduce treatment‐associated toxicity, offering a promising path for clinical translation.