Self-Assembled Ruthenium-Amino Acid Conjugates Enable Endoplasmic Reticulum-Nucleus Cascade Targeting for Cell
Zhiyuan Ma1,2, Maomao He1,3, Zongwei Zhang1
1State Key Laboratory of Fine Chemicals, Frontiers Science Center for Smart Materials Oriented Chemical Engineering, Dalian University of Technology, Dalian, 116024, China.
Abstract:
The distinct photophysical and photochemical properties of ruthenium (Ru) complexes have made them potent therapeutic agents in photodynamic therapy (PDT) and photoactivated chemotherapy (PACT) for tumors. Simple synthesis, precise self-assembly delivery and specific subcellular distribution are essential for Ru complexes but remain significant challenges. Herein, a simple building block, Fmoc-methionine (Fmoc-M), is directly coordinated with a Ru center to construct a pH and light responsive Ru-amino acid conjugate (FmocRu), which directly self-assembles into nanoparticles, thus avoiding using polymeric and inorganic nanocarriers. Upon accumulation at the tumor site, the acidic microenvironment protonated the carboxyl groups in the amino acids, disrupting the supramolecular force balance and reducing particle size to enhance tumor penetration. The newly-formed small nanospheres exhibit programmable cascade targeting by first accumulating in the endoplasmic reticulum, then rapidly disassembling upon light irradiation to enable nuclear delivery of the released Ru complexes. This feature enabled FmocRu to induce cell death via the pyroptosis pathway and DNA damage. As a result, the Ru conjugate eliminated subcutaneous tumors and suppressed orthotopic breast tumor growth and metastasis in tumor-bearing mice model, offering a valuable platform to develop Ru complexes for anticancer research in PDT and PACT.
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