Advanced Science Research Center at The Graduate Center of the City University of New York, 85 Saint Nicholas Terrace, New York, NY, 10031, USA.
Department of Chemistry and Biochemistry, The City College of New York, 1024 Marshak, 160 Convent Avenue, NY, 10031, USA.
Adv Mater. 2022 Jan;34(1):e2104962. doi: 10.1002/adma.202104962. Epub 2021 Oct 20.
Supramolecular self-assembly in biological systems holds promise to convert and amplify disease-specific signals to physical or mechanical signals that can direct cell fate. However, it remains challenging to design physiologically stable self-assembling systems that demonstrate tunable and predictable behavior. Here, the use of zwitterionic tetrapeptide modalities to direct nanoparticle assembly under physiological conditions is reported. The self-assembly of gold nanoparticles can be activated by enzymatic unveiling of surface-bound zwitterionic tetrapeptides through matrix metalloprotease-9 (MMP-9), which is overexpressed by cancer cells. This robust nanoparticle assembly is achieved by multivalent, self-complementary interactions of the zwitterionic tetrapeptides. In cancer cells that overexpress MMP-9, the nanoparticle assembly process occurs near the cell membrane and causes size-induced selection of cellular uptake mechanism, resulting in diminished cell growth. The enzyme responsiveness, and therefore, indirectly, the uptake route of the system can be programmed by customizing the peptide sequence: a simple inversion of the two amino acids at the cleavage site completely inactivates the enzyme responsiveness, self-assembly, and consequently changes the endocytic pathway. This robust self-complementary, zwitterionic peptide design demonstrates the use of enzyme-activated electrostatic side-chain patterns as powerful and customizable peptide modalities to program nanoparticle self-assembly and alter cellular response in biological context.
在生物系统中，超分子自组装有望将疾病特异性信号转化和放大为物理或机械信号，从而指导细胞命运。然而，设计具有生理稳定性、可调谐和可预测行为的自组装系统仍然具有挑战性。本文报道了在生理条件下使用两性离子四肽模式来指导纳米颗粒组装。通过基质金属蛋白酶-9（MMP-9）酶促揭示表面结合的两性离子四肽，可以激活金纳米颗粒的自组装，MMP-9 在癌细胞中过表达。这种强大的纳米颗粒组装是通过两性离子四肽的多价、自互补相互作用实现的。在过表达 MMP-9 的癌细胞中，纳米颗粒组装过程发生在细胞膜附近，并导致大小诱导的细胞摄取机制选择，从而减少细胞生长。通过定制肽序列，可以编程该系统的酶反应性，从而间接编程其摄取途径：在酶切位点处简单地反转两个氨基酸完全使酶反应性、自组装失活，从而改变内吞途径。这种强大的自互补两性离子肽设计证明了使用酶激活的静电侧链模式作为强大且可定制的肽模式来编程纳米颗粒自组装并改变生物环境中的细胞反应。
