An Acidosis-Activatable Nanocomposite for Synergistic Microenvironment Remodeling and Reprogramming of Innate–Adaptive Immune Crosstalk in Rheumatoid Arthritis

Immunotherapy offers great potential for treating autoimmune diseases such as rheumatoid arthritis (RA); however, its efficacy is constrained by the pathological RA microenvironment. This microenvironment is perpetuated by a maladaptive innate–adaptive immune crosstalk, in which sustained M1 macrophage polarization from the innate immune system disrupts the Treg/Th17 balance, further reinforcing aberrant M1 activation. In addition, excessive reactive oxygen species (ROS) and acidosis exacerbate inflammatory damage. To address these challenges, we developed a bone-targeting nanocomposite, CaO 2 /CeO 2 @ZIF-8-ALN-AOA (CCZ-AA), to remodel the microenvironment and restore immune homeostasis by comodulating innate and adaptive immunity. Under acidic conditions, CCZ-AA disassembles and exerts dual regulatory effects: (i) CaO 2 /CeO 2 neutralizes excess H +, alleviates acidosis, generates oxygen, and enhances the antioxidant activity of CeO 2, thereby promoting M1-to-M2 macrophage repolarization; and (ii) the released AOA facilitates Treg differentiation to rebalance the Treg/Th17 axis, while Tregs further stabilize M2 polarization, forming a reciprocal “Treg–M2” regulatory loop. In a collagen-induced arthritis mouse model, CCZ-AA markedly increased Treg levels in the spleen and synovium and mitigated joint destruction. These findings highlight the potential of CCZ-AA as a promising immunoregulatory strategy for RA by reprogramming the inflammatory microenvironment and restoring immune equilibrium.