Dual-Stimuli-Responsive Nanoplatform Delivering Molecular Glue CR8 for Synergistic CDK12 Degradation and Immunomodulatory Photothermal Therapy in TNBC

The clinical translation of the molecular glue CR8, a potent CDK12/CCNK degrader for reversing TNBC immunosuppression, is severely hampered by its poor solubility and off-target toxicity. To surmount these challenges, we engineered an intelligent nanoplatform, ZCPc, for synergistic chemo-photothermal-immunotherapy. Leveraging the intrinsic structural mimicry between the imidazole framework of the ZIF-8 core and the CR8 molecule, we achieved efficient drug loading. This core is coated with polydopamine (PDA) as a photothermal agent and gatekeeper, and functionalized with c(RGDfK) for active targeting. The nanoplatform exhibits a dual-stimuli-responsive release mechanism, being first destabilized by the acidic tumor microenvironment and subsequently disrupted upon external near-infrared (NIR) irradiation, ensuring spatiotemporally precise CR8 delivery. Critically, we uncovered a profound mechanistic synergy. While PDA-mediated photothermal therapy (PTT) induced robust immunogenic cell death (ICD), it concurrently triggered a compensatory immunosuppressive feedback loop via PD-L1 upregulation. Remarkably, the precisely released CR8 counteracted this adaptive resistance by inducing CDK12 degradation and subsequently downregulating PD-L1, effectively converting ″cold″ tumors into ″hot″ ones. This combinatorial therapy fundamentally remodeled the tumor immune microenvironment, effectively reversing immunosuppression and activating a potent antitumor immune response. By integrating targeted chemotherapy, PTT, and immunotherapy through this unique synergistic axis, the ZCPc nanoplatform presents a potent paradigm for eliciting effective antitumor immune responses in TNBC.