Bimetallic nanodot-adenovirus chimera for cancer theranostics via cooperativity of autophagy and ferroptosis

<h2>Summary</h2> The application of oncolytic adenoviruses (Ads) is hampered by the inability to target tumor sites via intravenous injection as well as insufficient intratumoral viral replication efficiency. To overcome these challenges, we report bimetallic nanodot-Ad chimeras (Ads@Gd/Fe-NDs) that enable targeted delivery and enhanced Ad replication via cooperativity of autophagy and ferroptosis against tumors. The systemic delivery of Ads@Gd/Fe-NDs leads to a high accumulation of Ads in tumors. Intratumorally released Fe³⁺ from chimeras induces ferroptosis within cancer cells, generating reactive oxygen species and activating cellular autophagy. The excessive enrichment of autophagy-induced autophagosomes elevates Ad replication efficiency in infected tumor cells, further resulting in overactivation of autophagy and amplifying autophagy-dependent ferroptosis. In addition, Gd³⁺ from Ads@Gd/Fe-NDs is released in response to the tumor microenvironment, serving intratumoral MRI in preclinical tumor-bearing mouse models. Collectively, such a nanodot-oncolytic virus chimera represents a potent translational platform for cancer theranostics.