Clinical bottom line
RNA interference (RNAi) therapies represent an emerging class of targeted treatments with potential applications in infectious diseases, including viral infections. While RNAi-based therapeutics offer a novel mechanism to selectively silence pathogen or host genes critical for infection, their clinical use raises unique considerations for infection risk management. Current evidence on infection susceptibility in patients receiving RNAi therapies is limited and largely preclinical or early-phase. Clinicians should be aware of the putative immunomodulatory effects of RNAi agents and the potential for altered host-pathogen interactions, warranting careful monitoring and individualized infection prevention strategies pending further clinical validation.
What the evidence shows
RNA interference is a conserved cellular mechanism that uses small interfering RNAs (siRNAs) to mediate sequence-specific degradation of target mRNA, thereby silencing gene expression (SpringerReference, 2023). This mechanism has been harnessed to develop RNAi-based nanomedicines targeting viral pathogens by inhibiting essential viral genes or host factors required for viral replication (Handbook of Harnessing Biomaterials in Nanomedicine, 2012). For example, RNAi approaches have been explored experimentally against SARS-CoV-2, with the goal of reducing viral load by targeting viral nonstructural proteins such as RNA-dependent RNA polymerase (Santos Bravo et al., 2022).
Despite promising antiviral activity, RNAi therapies may influence host immune responses. The intracellular delivery of siRNAs can activate innate immune sensors or alter cytokine profiles, potentially modulating susceptibility to secondary infections (SpringerReference, 2023). Although direct clinical data on infection risk in patients receiving RNAi therapeutics remain sparse, parallels can be drawn from experience with other novel biologics, such as anti-TNF agents, which have been associated with increased risk of mycobacterial and opportunistic infections (Winthrop et al., 2008).
The pharmacokinetics and biodistribution of RNAi nanomedicines may also affect infection risk by altering immune cell function in target tissues (Handbook of Harnessing Biomaterials in Nanomedicine, 2012). Furthermore, the phenomenon of transitive RNA interference, where secondary siRNAs amplify gene silencing beyond the initial target, raises theoretical concerns about off-target effects impacting host defense genes (Dictionary of Genomics, Transcriptomics and Proteomics, 2015).
Caveats and uncertainty
The clinical evidence base for infection management in patients receiving RNAi therapies is currently limited to preclinical and early-phase studies, with no large-scale clinical trials definitively characterizing infection risks or management protocols. The immunomodulatory effects of RNAi agents are complex and may vary depending on delivery platforms, target genes, and patient-specific factors. Additionally, the long-term consequences of RNAi-mediated gene silencing on host immunity remain incompletely understood.
Given the novelty of RNAi therapeutics, existing clinical guidelines do not yet provide specific recommendations for infection screening, prophylaxis, or monitoring in this population. Extrapolation from other biologic therapies is imperfect due to mechanistic differences. Therefore, clinicians should exercise caution and consider individualized risk assessments, especially in patients with preexisting immunosuppression or comorbidities.
How this may change practice
As RNAi therapies gain clinical approval and wider use, infectious disease clinicians will need to integrate knowledge of RNAi mechanisms into infection risk assessment and management. This includes heightened vigilance for atypical or opportunistic infections, consideration of baseline immune status, and potential interactions with concomitant immunomodulatory treatments.
Incorporation of RNAi therapy status into antimicrobial stewardship and infection prevention protocols may become necessary. Multidisciplinary collaboration with treating specialists and pharmacologists will be important to optimize patient outcomes. Future clinical trials and real-world studies should prioritize systematic infection surveillance and reporting to inform evidence-based guidelines.