A Spatiotemporally Controlled Nanoplatform for Photothermal BRD4 Degradation Enables Synergistic Cancer Immunotherapy

ABSTRACT Conventional targeted protein degradation (TPD) via PROTACs is limited by E3 ligase reliance and a lack of spatiotemporal control, often causing systemic toxicity. Here, we report a photothermolysis‐targeting conjugate (PTTAC) strategy for precise, light‐activated degradation. We constructed a multifunctional theranostic nanoplatform (PCN‐CuS‐JQ/RGD) based on an MRI‐visible, Fe‐porphyrin MOF (PCN(Fe)) carrier, decorated with CuS photothermal agents, a BRD4 inhibitor (JQ1), and a tumor‐targeting peptide (RGD). It executes a sophisticated step‐wise delivery: 1) The RGD peptide facilitates active targeting to integrin‐overexpressing tumor cells. 2) Upon internalization, the PCN(Fe) carrier decomposes within the cell, releasing smaller CuS‐JQ/RGD units. 3) These units enter the nucleus and bind to the BRD4 protein. Under 1064 nm (NIR‐II) laser irradiation, the localized photothermal effect generated by CuS induces the efficient degradation of BRD4. This PTTAC strategy not only inhibits tumor growth but also initiates a robust anti‐tumor immune response by inducing immunogenic cell death (ICD) and downregulating PD‐L1 expression. Crucially, in a bilateral tumor‐bearing mouse model, our strategy demonstrated a powerful synergistic effect, significantly enhancing the efficacy of anti‐PD‐L1 immune checkpoint blockade therapy. This work presents a light‐activatable degradation platform that achieves high tumor selectivity and potent immunotherapy, offering a promising new avenue for cancer treatment.