NIR‐II Imaging‐Guided Photothermal Activation of a TRPV4‐Targeted Nanoplatform Delivering Cycloastragenol to Promote Microglia Reprogramming and α‐Synuclein Clearance in Parkinson's Disease

ABSTRACT Current therapies for Parkinson's disease (PD) fail to concurrently address α ‐synuclein ( α ‐syn) aggregation and microglia‐mediated neuroinflammation. Herein, we engineer a near‐infrared‐II (NIR‐II) phototheranostic nanoplatform, CAG/FD1080@MM‐aTRPV4, for synergistic regulation of microglial function and real‐time monitoring of PD pathology. We first encapsulated cycloastragenol (CAG), a bioactive compound derived from Astragalus , into liposomes. These liposomes were then fused with biomimetic microglial membrane‐loaded FD1080 photothermal imaging agent, followed by modification with a transient receptor potential vanilloid 4 (TRPV4)‐targeting antibody. In vitro studies using α ‐syn‐treated cultured microglia and in vivo studies in an α ‐syn‐overexpressing mouse model collectively demonstrate the efficacy of our strategy. It not only enables precise microglial delivery of CAG to reprogram metabolism but also sustains lysosomal function via photothermal activation of the TRPV4/CaMKK β /AMPK/mTOR pathway, ultimately enhancing phagocytosis. Importantly, the encapsulated FD1080 (for microglial tracking) and an anti‐ α ‐syn‐conjugated indocyanine green (anti‐ α ‐syn‐ICG) probe enable dual‐modality NIR‐II photoacoustic‐fluorescence imaging, allowing real‐time visualization of both microglial dynamics and α ‐syn clearance. This work pioneers a photothermal immunomodulation strategy using a Chinese herb‐derived compound, presenting a versatile theranostic platform and novel mechanistic insights for microglia‐targeted PD therapy.