Enhance Efferocytosis and Block the Macrophages–Platelets Feedback Loop for Targeted Treatment of Psoriasis

Efferocytosis of macrophages infiltrated in psoriatic lesions is mostly impaired, thus promoting the progression of psoriasis. Herein, we reveal that there exists a feedback loop between activated platelets and efferocytosis-impaired macrophages in psoriatic. Or rather, efferocytosis-impaired macrophages stimulate platelet activation, which in turn down-regulates the expression of the phagocytic receptor Mer on macrophages and polarizes macrophages to the M1-phenotype of weaker efferocytosis ability. Therefore, we construct a combined nanoplatform for more precise targeting to efferocytosis-impaired macrophages and activated platelets. The macrophage-targeting part of the nanoplatform efficiently orientates to efferocytosis-impaired macrophages through macrophage membrane encapsulation and targeting peptide modification. This increases the expression of Mer, simultaneously enhances the acidification and maturation of efferosomes, ultimately restores efferocytosis of macrophages, and promotes the phagocytosis and clearance of apoptotic cells. On the other hand, the activated platelet-targeting nanoparticles inhibit the activation of platelets, thus blocking the feedback loop and eventually preventing the down-regulation of Mer expression on macrophages. Furthermore, the combined nanoplatform suppresses the infiltration of macrophages and platelets in psoriatic lesions, reduces the release of pro-inflammatory factors such as IL-17A, and consequently improves the therapeutic effect of psoriasis and prevention of its recurrence <i>in vivo</i>. Collectively, this two-pronged strategy with multifunctionality in repairing efferocytosis, inhibiting platelet activation, and blocking the feedback loop may provide options available for the treatment of psoriasis.