Tumor microenvironment-triggered aggregation of semiconducting polymer nanochangers for self-programable theranostics of orthotopic glioma

<b>Rationale:</b> Nanotheranostics have attracted significant research attention for their potential in improving glioma management through integrated diagnostic and therapeutic functions. However, the limited capacity for dynamic structural transformation of current nanotheranostics in the tumor microenvironment (TME) restricts theranostic outcomes. <b>Methods:</b> Herein, we report a semiconducting polymer (SP)-based nanochanger (TM-P@SPN) that demonstrates aggregation-enhanced self-programable theranostics in orthotopic glioma upon glutathione (GSH) response. The TM-P@SPN is prepared using a SP as a triple-functional component (fluorescence probe, second near-infrared photoacoustic probe, and photothermal sensitizer), <i>β</i>-amyloid peptide domain (KLVFF)-linked PEG as an aggregation trigger switch, and transferrin modified manganese dioxide (TM) as a targeting theranostic agent. <b>Results:</b> Upon GSH response in the TME, the TM-P@SPN disassembles to release PEG and Mn (II), enabling SP-KLVFF-mediated hydrophobic aggregation through hydrogen bonding, which consequently enhances both photoacoustic imaging (PAI) and photothermal therapy (PTT). Meanwhile, the released Mn(II) can be utilized for <i>T</i> ₁-weighted magnetic resonance imaging (MRI) and chemodynamic therapy (CDT). Moreover, both CDT- and PTT-induced immunogenic cell death effect and Mn(II)-activated STING pathway promote dendritic cells maturation, thereby triggering systemic immune effects. <b>Conclusions:</b> This TME-responsive nanochanger is successfully used for self-programable theranostics, including fluorescence imaging (FLI)-enhanced PAI-MRI and CDT-enhanced PTT-immunotherapy.