A Membrane-Anchoring Self-Assembling Peptide Allows Bioorthogonal Coupling of Type-I AIEgens for Pyroptosis-Induced
Shenglu Ji1, Tengwu Pan2, Kaiyuan Wang1
1The Key Laboratory of Biomedical Materials, School of Life Science and Technology, Xinxiang Medical University, Xinxiang, 453003, China.
Abstract:
Enrichment of photosensitizers (PSs) on cancer cell membranes via bioorthogonal reactions is considered to be a very promising therapeutic modality. However, azide-modified sugars-based metabolic labeling processes usually lack targeting and the labeling speed is relatively slow. Moreover, it has been rarely reported that membrane-anchoring pure type-I PSs can induce cancer cell pyroptosis. Here, we report an alkaline phosphatase (ALP) and cholecystokinin-2 receptor (CCK2R) dual-targeting peptide named DBCO-pYCCK6, which can selectively and rapidly self-assemble on cancer cell membrane, and then bioorthogonal enrich type-I aggregation-induced emission luminogens (AIEgen) PSs (SAIE-N3) on the cell membrane. Upon light irradiation, the membrane-anchoring SAIE-N3 could effectively generate type-I reactive oxygen species (ROS) to induce gasdermin E (GSDME)-mediated pyroptosis. In vivo experiments demonstrated that the bioorthogonal combination strategy of peptide and AIEgen PSs could significantly inhibit tumor growth, which is accompanied by CD8+ cytotoxic T cell infiltration. This work provides a novel self-assembly peptide-mediated bioorthogonal reaction strategy to bridge the supramolecular self-assembly and AIE field through strain-promoted azide-alkyne cycloaddition (SPAAC) and elucidates that pure type-I membrane-anchoring PSs can be used for cancer therapy via GSDME-mediated pyroptosis.
Insights
This study introduces a dual-targeting peptide for rapid, targeted enrichment of photosensitizers on cancer cell membranes, enabling efficient pyroptosis induction and tumor inhibition via reactive oxygen species generation.
Area of Science:
- Biomedical Engineering
- Cancer Therapy
- Supramolecular Chemistry
Background:
- Photosensitizer enrichment on cancer cell membranes via bioorthogonal reactions is promising but often lacks targeting and speed.
- Existing azide-modified sugar labeling methods are slow and non-specific.
- Membrane-anchoring pure type-I photosensitizers rarely induce cancer cell pyroptosis.
Purpose of the Study:
- To develop a dual-targeting peptide for rapid, selective cancer cell membrane enrichment of photosensitizers.
- To investigate the induction of gasdermin E-mediated pyroptosis using membrane-anchoring type-I photosensitizers.
- To evaluate the in vivo efficacy of this bioorthogonal combination strategy for cancer therapy.
Main Methods:
- Design and synthesis of a dual-targeting peptide (DBCO-pYCCK6) for alkaline phosphatase (ALP) and cholecystokinin-2 receptor (CCK2R).
- Bioorthogonal enrichment of azide-modified aggregation-induced emission luminogen (AIEgen) photosensitizers (SAIE-N3) on cancer cell membranes via strain-promoted azide-alkyne cycloaddition (SPAAC).
- In vitro assessment of pyroptosis induction and in vivo tumor growth inhibition studies.
Main Results:
- The DBCO-pYCCK6 peptide selectively and rapidly self-assembled on cancer cell membranes.
- Membrane-anchored SAIE-N3 generated type-I reactive oxygen species (ROS) upon light irradiation, inducing GSDME-mediated pyroptosis.
- In vivo studies showed significant tumor growth inhibition and increased CD8+ cytotoxic T cell infiltration.
Conclusions:
- A novel peptide-mediated bioorthogonal strategy enables supramolecular self-assembly and AIEgen enrichment for cancer therapy.
- Pure type-I membrane-anchoring photosensitizers can effectively induce GSDME-mediated pyroptosis for cancer treatment.
- This approach offers a promising new avenue for targeted cancer therapy by combining bioorthogonal chemistry and pyroptosis induction.
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