Macrofungi as Antiviral Agents: Mechanisms of Action, Comparative Evidence, and Translational Challenges

The 2025 emergence of a hypervirulent human metapneumovirus (HMPV) strain in China, with a 22% ICU mortality rate and transmission rate ( R 0 ) of 1.4, has exposed critical vulnerabilities in antiviral defenses. This review argues that medicinal mushrooms, rich in pleiotropic bioactives, present a promising solution to core challenges in viral control: immune evasion, rapid mutation, and limited treatment accessibility. We synthesize evidence that fungal polysaccharides (e.g., lentinan) and triterpenoids (e.g., ganoderic acids) function as multitarget therapeutics, inhibiting viral entry (IC 50 : 0.16–4 μg/mL for HMPV RdRp), reducing cytokine storms (>50% IL‐6 reduction in murine models), and enhancing NK cell cytotoxicity (40%–60% increase). Unlike single‐target antivirals such as remdesivir, mushroom‐derived agents exhibit a low resistance profile due to host‐directed mechanisms. Clinical translation, however, remains limited by extract variability (up to 300% difference in β‐glucan content) and an evidence gap; none of the 12 registered trials targets HMPV. We propose a “Mycotherapeutic Development Pipeline” integrating AI‐guided discovery, CRISPR‐enhanced fungal strains (7.3‐fold increase in cordycepin yield), and nanoparticle delivery (92% encapsulation efficiency). Regulatory modernization is essential to position mushroom‐derived adjuvants as first‐line therapeutics against emerging Pneumoviridae threats.