Nanoparticle-Virus Chimeras for Tissue-Specific Systemic Delivery

Nanotherapeutic delivery to specific cells and tissues remains a critical roadblock in disease treatment and typically relies on bespoke targeting strategies (e.g., antibodies, peptides). Despite many advancements, the efficiency of delivery into the brain generally remains ≤1% of the injected dose per brain mass (% ID/g brain), and significant off-target accumulation is frequently observed in the liver.
Viruses have evolved to effectively target specific tissues, and this tropism is leveraged for gene delivery and therapy. Adeno-associated viruses (AAVs) are widely preferred as gene delivery vectors owing to their low immunogenicity and non-pathogenicity, and have been engineered to produce serotype libraries that target diverse cell classes. For example, the brain-targeting serotype AAV-PHP.eB was shown to achieve ~33% ID/g brain. More recently, AAV.CAP-B10 demonstrated even greater efficiency and specificity of transgene delivery to the brain with minimal liver accumulation.
In this study, we report a generalizable approach for nanomaterials delivery by coupling them to AAVs that exhibit tissue-specific tropism. Utilizing the inverse electron-demand Dials Alder cycloaddition, we synthesize chimeras composed of AAVs and magnetic nanoparticles (MNPs). Our method enables precise control over AAV-MNP stoichiometry and can be applied to different AAV serotypes and various classes of nanomaterials. In vitro, these MNP-AAV chimeras selectively escort nanoparticles into specific cells according to the tropism of AAVs. Furthermore, magnetic moments of these chimeras allow spatially restricted cellular uptake and localized gene delivery. In vivo, we apply chimeras to guide MNPs into the brain. By coupling MNPs to a brain-targeting AAV serotype, we achieve delivery efficiency of ~10% ID/g brain, a delivery efficiency more than 10-fold higher than prior reports for nanomaterials (<1% ID/g brain). Notably, the gene delivery function of AAVs is retained after conjugation to MNPs. Our findings highlight the potential of AAVs as targeting agents for delivery of nanotherapeutics to the tissues and organs of interest.