(1) Journal Source: Advanced Materials


(2) Title: Protein Degradation Nanoparticles for Intraoperative Fluorescence Diagnosis and Postoperative Adjuvant Therapy of Solid Tumors


(3) Research Highlights: In this work, sequentially responsive theranostic chimeric SEQTAC nanoparticles were designed. Cysteine cathepsin B-activatable fluorophores were covalently conjugated with BRD4-PROTAC modified by singlet oxygen-sensitive linkages. The nanoparticles can be administered via local spraying. Through sequential enzyme-photo activation, their performance in intraoperative fluorescence imaging-guided navigation and postoperative residual tumor intervention was investigated at the cellular level and in animal models of breast cancer and glioblastoma.


(4) Innovations: ① A sequentially activated SEQTAC nanotheranostic system was constructed. The nanoparticles are formed via molecular self-assembly without additional carriers; ② A two-step cascade response is realized: cathepsin B triggers fluorescence turn-on for intraoperative tumor boundary identification, and near-infrared light generates singlet oxygen to cleave the linkage and release PROTAC; ③ Local spray administration at the surgical site is adopted to circumvent pharmacokinetic timing challenges caused by systemic administration; ④ Photodynamic therapy synergizes with BRD4 protein degradation to exert therapeutic intervention against postoperative residual tumors.


(5) Material Development
(1) Materials: The ATHC molecule was constructed using HCy-Br hemicyanine fluorophore-photosensitizer, TK thioketal bond, BRD4-targeted PROTAC (ARV771), and cathepsin B-cleavable Cit-Val peptide. SEQTAC nanoparticles were obtained via self-assembly.


(2) Functions: Fluorescence is restored in response to cathepsin B to enable intraoperative tumor tracing; irradiation at 655 nm generates singlet oxygen, which yields photodynamic effects and cleaves TK bonds to release PROTAC; BRD4 target protein degradation is achieved to induce tumor cell apoptosis; the formulation is compatible with local spray administration and possesses tumor tissue penetration capacity.

(6) Outlook: Probes can be remodeled by screening biomarkers with superior tumor specificity to reduce signal interference from inflammatory cells; the molecular structure can be further optimized to improve photoresponse kinetics; this sequential activation strategy can be expanded to accommodate more PROTACs and bioactive molecules.

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