Psoriatic self-antigen LL37 has the ability to stimulate skin-homing T lymphocytes, which is the constitutive factor for the relapse of psoriasis. The local inflammatory modulation in psoriatic skin is not sufficient for the restoration of immune homeostasis. In this study, we found the expression levels of disease specific proteins including LL37, S100A8 and S100A9 were significantly increased in psoriasis. The self-assembled nanoparticles based on methoxy-poly(ethylene glycol)-block-poly(L-histidine) and methoxy-poly(ethylene glycol)-block-poly(L-lactic acid) (HLNPs) were capable of interacting and absorbing these disease specific proteins, leading to the accumulation of HLNPs in peripheral inflammatory immune cells. Therefore, we proposed an “Antigen-scavenging” polypeptide nano-system assembled from the “sandwich” structure composed of HLNPs, siRNA-TNFα, and oligolysine conjugated methotrexate prodrug (HLNP-MNs), with the encapsulation of ROS-responsive methotrexate prodrug and siRNA-TNFα. We evaluated the biological fate of HLNP-MNs in vivo, the ROS-responsive release of methotrexate (MTX) and siRNA-TNFα in inflammatory immune cells, the suppression of immune response triggered by autoantigen LL37 and the inhibition of skin-homing T lymphocytes from the aspects of “nanoparticle-protein” interaction, cellular level and mouse models. The design of “Antigen-scavenging” polypeptide nanoparticles with loading of MTX and siRNA-TNFα, can shed light on restoring immune homeostasis in psoriasis.