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Published on: February 27, 2019
Peptide-Driven Proton Sponge Nano-Assembly for Imaging and Triggering Lysosome-Regulated Immunogenic Cancer Cell
Tengyu He1, Jing Wen2, Wenjian Wang3
1Program in Materials Science and Engineering, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA.
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.
Insights
Novel proton sponge nano-assemblies (PSNAs) trigger cancer cell death and activate anti-tumor immunity. These engineered nanomedicines offer a promising strategy for overcoming "immune-cold" tumors in cancer immunotherapy.
Area of Science:
- Nanomedicine
- Cancer Immunotherapy
- Cell Death Mechanisms
Background:
- Nanomedicines can induce immunogenic cell death (ICD) to convert "immune-cold" tumors to "immune-hot" for enhanced cancer immunotherapy.
- Proton sponges like polyethylenimine (PEI) rupture lysosomes but exhibit uncontrollable toxicity and unclear cell death mechanisms.
Purpose of the Study:
- To develop novel proton sponge nano-assemblies (PSNAs) with controllable surface charge density and cytotoxicity.
- To investigate the cell death mechanisms triggered by PSNAs and their potential in cancer immunotherapy.
Main Methods:
- Constructed PSNAs using low-molecular-weight branched PEI covalently linked to self-assembling peptides functionalized with tetraphenylethene pyridinium (PyTPE).
- Optimized PSNA self-assembly by tuning peptide hydrophilicity/hydrophobicity to enhance fluorescence, charge density, cell uptake, and cytotoxicity.
- Conducted systematic studies to elucidate cell death pathways induced by PSNAs.
Main Results:
- Created PSNAs with tunable surface charge density and enhanced cancer cell cytotoxicity.
- Demonstrated that PSNAs trigger lysosome-rupturing-mediated pyroptosis and necroptosis.
- Showed that PSNA-induced ICD in tumor cells activates immune cells.
Conclusions:
- PSNAs represent a promising nanomedicine platform for triggering ICD and overcoming challenges in cancer immunotherapy.
- The developed PSNAs effectively induce pyroptosis and necroptosis, leading to anti-tumor immune responses.
