Nerve growth factor-targeting nanocluster-antibody-drug conjugates for intravesical precision theranostics of interstitial cystitis.

Interstitial cystitis (IC) is a chronic inflammatory bladder disorder lacking timely diagnostic and therapeutic options. Here, we propose a unitary theranostic nanocluster-antibody-drug conjugate (NADC) by covalently attaching dihydroorotate dehydrogenase inhibitors (DHODHi) and ultrasmall gold quantum clusters (AuQCs) to a nerve growth factor (NGF) antagonistic antibody, with multimodality imaging contrasts. Combining anti-inflammatory effects from all individual components, intravesical NADC specifically homed to mucosal lesions with tissue-residing NGF overexpression in the voided bladder, where it neutralized and formed immunocomplexes with secreted NGF to be intracellularly internalized by inflammatory macrophages for payload release through the FcγR-mediated pathway. NADC alleviated inflammation in chronic, acute, and prophylactic IC models of rats, as revealed by behavioral and pathological evaluations. Transcriptomics unveiled cytokine modulation and concomitant inhibition of perturbed IL-17, NF-κB, TNF, and JAK-STAT signaling pathways. Notably, NADC indirectly remodeled the host bladder microbiota by differentially varying anti-inflammatory and pro-inflammatory bacterial diversities. Distinct from conventional nanoparticles conjugated with antibodies or drugs, NADC relies on the antibody framework, outperforms clinical standard-of-care agents, and represents emerging precision medicine with translational potential for IC theranostics in clinical practice.