Rapamycin-encapsulated costimulatory ICOS/CD40L-bispecific nanoparticles restrict pathogenic helper T-B-cell interactions while in situ suppressing mTOR for lupus treatment.

Excessive CD4 T helper (Th)-B-cell interactions and loss of Treg homeostasis are crucial to the pathogenesis of systemic lupus erythematosus (SLE). Targeting the SLE-specific upregulated costimulatory molecules ICOS or CD40L on Th can block Th-B reciprocal activation, but single costimulatory molecular blockade exhibited unsatisfactory therapeutic efficacy due to pathway redundancy. As ICOS and CD40L nonredundantly and cooperatively promote Th-B-cell reciprocal activation, simultaneously blocking ICOS and CD40L may achieve a synergistic effect. Moreover, inhibition of overactivated mTOR signaling by rapamycin (RAP) can promote Treg expansion while restraining autoreactive T-B-cell activation, which can work as an adjuvant to pair with costimulation blockade to restore immune homeostasis. However, systemic administration of multiple immune modulators is hindered by limited drug enrichment at the target site and increased systemic toxicity. Here, we rationally designed RAP-encapsulated ICOS/CD40L bispecific nanoparticles (NPs) to achieve multitarget therapy in a disease-specific manner. Through ex vivo cocultures of Th and B cells from SLE mice or patients and in vivo SLE mouse models, we demonstrated that RAP-encapsulated ICOS/CD40L bispecific NPs selectively target SLE Th cells and potently inhibit Th-B-cell reciprocal activation by targeting dual costimulatory pathways. In addition, the sustained release of RAP benefits from the precise targeting ability of bispecific NPs to further inhibit in situ Th-B cells while promote bystander Treg cells, which help to significantly alleviate SLE progression in both inducible and spontaneous lupus models with no obvious toxicity.