An official website of the United States government
Abstract Triggering lysosome‐regulated immunogenic cell death (ICD, e.g., pyroptosis and necroptosis) with nanomedicines is an emerging approach for turning an “immune‐cold” tumor “hot”—a key challenge faced by cancer immunotherapies. Proton sponge such as high‐molecular‐weight branched polyethylenimine (PEI) is excellent at rupturing lysosomes, but its therapeutic application is hindered by uncontrollable toxicity due to fixed charge density and poor understanding of resulted cell death mechanism. Here, a series of proton sponge nano‐assemblies (PSNAs) with self‐assembly controllable surface charge density and cell cytotoxicity are created. Such PSNAs are constructed via low‐molecular‐weight branched PEI covalently bound to self‐assembling peptides carrying tetraphenylethene pyridinium (PyTPE, an aggregation‐induced emission‐based luminogen). Assembly of PEI assisted by the self‐assembling peptide‐PyTPE leads to enhanced surface positive charges and cell cytotoxicity of PSNA. The self‐assembly tendency of PSNAs is further optimized by tuning hydrophilic and hydrophobic components within the peptide, thus resulting in the PSNA with the highest fluorescence, positive surface charge density, cell uptake, and cancer cell cytotoxicity. Systematic cell death mechanistic studies reveal that the lysosome rupturing‐regulated pyroptosis and necroptosis are at least two causes of cell death. Tumor cells undergoing PSNA‐triggered ICD activate immune cells, suggesting the great potential of PSNAs to trigger anticancer immunity.
more »
« less
Combined Tumor Environment Triggered Self‐Assembling Peptide Nanofibers and Inducible Multivalent Ligand Display for Cancer Cell Targeting with Enhanced Sensitivity and Specificity
Abstract Many new technologies, such as cancer microenvironment‐induced nanoparticle targeting and multivalent ligand approach for cell surface receptors, are developed for active targeting in cancer therapy. While the principle of each technology is well illustrated, most systems suffer from low targeting specificity and sensitivity. To fill the gap, this work demonstrates a successful attempt to combine both technologies to simultaneously improve cancer cell targeting sensitivity and specificity. Specifically, the main component is a targeting ligand conjugated self‐assembling monomer precursor (SAM‐P), which, at the tumor site, undergoes tumor‐triggered cleavage to release the active form of self‐assembling monomer capable of forming supramolecular nanostructures. Biophysical characterization confirms the chemical and physical transformation of SAM‐P from unimers or oligomers with low ligand valency to supramolecular assemblies with high ligand valency under a tumor‐mimicking reductive microenvironment. The in vitro fluorescence assay shows the importance of supramolecular morphology in mediating ligand–receptor interactions and targeting sensitivity. Enhanced targeting specificity and sensitivity can be achieved via tumor‐triggered supramolecular assembly and induces multivalent ligand presentation toward cell surface receptors, respectively. The results support this combined tumor microenvironment‐induced cell targeting and multivalent ligand display approach, and have great potential for use as cell‐specific molecular imaging and therapeutic agents with high sensitivity and specificity.
more »
« less
- Award ID(s):
- 1824614
- PAR ID:
- 10454744
- Publisher / Repository:
- Wiley Blackwell (John Wiley & Sons)
- Date Published:
- Journal Name:
- Small
- Volume:
- 16
- Issue:
- 38
- ISSN:
- 1613-6810
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
-
Abstract 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.more » « less
-
Abstract Nanoparticles have drawn intense interest as delivery agents for diagnosing and treating various cancers. Much of the early success was driven by passive targeting mechanisms such as the enhanced permeability and retention (EPR) effect, but this has failed to lead to the expected clinical successes. Active targeting involves binding interactions between the nanoparticle and cancer cells, which promotes tumor cell-specific accumulation and internalization. Furthermore, nanoparticles are large enough to facilitate multiple bond formation, which can improve adhesive properties substantially in comparison to the single bond case. While multivalent binding is universally believed to be an attribute of nanoparticles, it is a complex process that is still poorly understood and difficult to control. In this review, we will first discuss experimental studies that have elucidated roles for parameters such as nanoparticle size and shape, targeting ligand and target receptor densities, and monovalent binding kinetics on multivalent nanoparticle adhesion efficiency and cellular internalization. Although such experimental studies are very insightful, information is limited and confounded by numerous differences across experimental systems. Thus, we focus the second part of the review on theoretical aspects of binding, including kinetics, biomechanics, and transport physics. Finally, we discuss various computational and simulation studies of nanoparticle adhesion, including advanced treatments that compare directly to experimental results. Future work will ideally continue to combine experimental data and advanced computational studies to extend our knowledge of multivalent adhesion, as well as design the most powerful nanoparticle-based agents to treat cancer.more » « less
-
Using Self-Assembling Peptides to Integrate Biomolecules into Functional Supramolecular BiomaterialsThroughout nature, self-assembly gives rise to functional supramolecular biomaterials that can perform complex tasks with extraordinary efficiency and specificity. Inspired by these examples, self-assembly is increasingly used to fabricate synthetic supramolecular biomaterials for diverse applications in biomedicine and biotechnology. Peptides are particularly attractive as building blocks for these materials because they are based on naturally derived amino acids that are biocompatible and biodegradable; they can be synthesized using scalable and cost-effective methods, and their sequence can be tailored to encode formation of diverse architectures. To endow synthetic supramolecular biomaterials with functional capabilities, it is now commonplace to conjugate self-assembling building blocks to molecules having a desired functional property, such as selective recognition of a cell surface receptor or soluble protein, antigenicity, or enzymatic activity. This review surveys recent advances in using self-assembling peptides as handles to incorporate biologically active molecules into supramolecular biomaterials. Particular emphasis is placed on examples of functional nanofibers, nanovesicles, and other nano-scale structures that are fabricated by linking self-assembling peptides to proteins and carbohydrates. Collectively, this review highlights the enormous potential of these approaches to create supramolecular biomaterials with sophisticated functional capabilities that can be finely tuned to meet the needs of downstream applications.more » « less
-
There is constant demand for new ligand archictectures on which inorganic and organometallic structures can be leveraged. An important, but often synthetically challenging, class of ligands is bidentate phosphines. Here we report self-assembling, supramolecular bidentate ligand scaffolds based on deconstructed Hamilton receptors with binding affinities up to 800 ± 100 M −1 .more » « less
