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              <p>It is still challenging to develop nanomedicines with full-active and simple components to tackle osteoarthritis (OA) through restoration of inflammation and cartilage homeostasis. Here, we report the synthesis of a bioactive asymmetric phosphorus dendrimer bearing an azabisphosphonate (ABP) group, termed as G0.PD-ABP, by a divergent method for intracellular bromelain (Bro) delivery. The formed G0.PD-ABP/Bro nanocomplexes (NCs) exhibit a uniformly dispersed spherical shape with a mean size of 148.4 nm and can achieve more significant intracellular Bro delivery than symmetric phosphorus dendrimer (G0.PD) without ABP via the clathrin-mediated endocytosis pathway. Importantly, the NCs efficiently block the activation of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and nuclear factor kappa-B (NF-κB) by amplifying the anti-inflammatory function of Bro and synergizing with the immunomodulatory activity of dendrimers, thereby facilitating the polarization of macrophages towards M2 phenotype and down-regulating inflammatory cytokine secretion to lead to suppressed chondrocyte apoptosis. Compared with G0.PD/Bro NCs, an OA mouse model treated with G0.PD-ABP/Bro NCs demonstrates more remarkable alleviation of pathological features such as cartilage degradation, bone erosion, and synovial inflammation. This study emphasizes the positive contribution of structural asymmetry of phosphorus dendrimers in protein delivery and provides a viable strategy for the treatment of OA or other inflammatory diseases through enhanced immune modulation of macrophages.</p>
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            <relation active="#struct-443875" type="indirect"/>
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        <org type="institution" xml:id="struct-67872" status="VALID">
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          <idno type="ROR">https://ror.org/05q3vnk25</idno>
          <orgName>Institut de Recherche pour le Développement</orgName>
          <orgName type="acronym">IRD</orgName>
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              <country key="FR"/>
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            <ref type="url">http://www.ird.fr/</ref>
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</TEI>