Artificially tagging tumors with nano-aluminum adjuvant-tethered antigen mRNA recruits and activates antigen-specific cytotoxic T cells for enhanced cancer immunotherapy.

T cell therapy for solid tumors faces significant challenges due to the immune off-target attack caused by the loss of tumor surface antigens and inactivation in acidic tumor microenvironment (TME). Herein, we developed a bifunctional immunomodulator (MO@NAL) by loading ovalbumin (OVA; model antigen) mRNA (mOVA) onto lysozyme-coated layered double hydroxide nano-aluminum adjuvant (NA). The NA's inherent alkalinity effectively neutralizes the excess acid within the TME and suppresses regulatory T cells, creating a favorable microenvironment to enhance cytotoxic T cell infiltration and activation in tumors. Particularly, once internalization by tumor cells, MO@NAL efficiently tags the tumor cell surface with OVA through the carried mOVA, providing targets for recruiting and directing the antigen-specific cytotoxic T cells to destroy tumor cells. In mice pre-vaccinated with the OVA vaccine, intratumoral administration of MO@NAL rapidly awakens OVA-specific immune memory, rapidly and effectively inhibiting the progression of colon tumors and melanoma at both early and advanced stages. In non-pre-vaccinated mice, combining MO@NAL with the OVA therapeutic vaccine or OVA-specific adoptive T cell transfusion similarly achieves robust solid tumor suppression. These findings thus underscore the potential of MO@NAL as an effective and safe immunomodulator for enhancing cytotoxic T cell responses and providing timely intervention in solid tumor progression.