BODIPY-Doped Nanocarrier Engineering (BONE) Improves Bone Marrow mRNA Delivery by NIR-II Bioimaging Guided Screening

Efficient delivery of mRNA to the bone marrow is crucial for maintaining immune homeostasis and understanding the pathogenesis of numerous disorders. However, achieving effective delivery remains challenging due to the low blood perfusion of bone tissue and the restrictive blood-bone marrow barrier. Conventional strategies for developing and screening bone-targeting carriers mainly rely on <i>in vitro</i> bone-binding assays and lack robust <i>in situ</i> evaluation tools. Here, we report a BODIPY-doped nanocarrier engineering (BONE) strategy that leverages NIR-II bioimaging for guided development and screening of mRNA delivery systems targeting the bone marrow. A library of NIR-II-emissive BODIPY dyes with intrinsic bone marrow tropism was doped onto lipid nanoparticles (LNPs) to construct BONE LNPs. Using NIR-II imaging, we achieve <i>in situ</i>, noninvasive, and real-time visualization of the bone-targeting capability of these LNPs prior to performing <i>in vivo</i> mRNA transfection studies. Among the formulations, BONE-2 LNPs demonstrate the highest bone accumulation at 24 h postinjection. Flow cytometry of bone marrow cells further reveal that BONE-2 LNPs preferentially localize to myeloid populations─including monocytes, macrophages, and dendritic cells─resulting in a 3.3-fold improvement in bone marrow mRNA transfection compared with a commercial LNP formulation. Together, this work establishes that integrating NIR-II BODIPY dyes into LNPs provides not only an effective strategy for targeted mRNA delivery to the bone marrow but also a generalizable framework for NIR-II imaging-guided screening of nanocarriers tailored to specific tissues.