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

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.