This study investigates the sequence-specific regulation of supramolecular chirality in amyloid-β42 (Aβ42) and its implications for designing tunable biomaterials. The research reveals that the central core of Aβ42, specifically the KLVFFAE sequence, exhibits sequence-specific chirality, with modifications at the C-terminus enabling chirality inversion at biologically relevant temperatures. The study demonstrates that C-terminal modifications can tune the energy barrier for left-to-right chiral inversion, allowing temperature-triggered chiral inversion of peptides hosting therapeutic payloads to modulate drug release. These findings suggest a generalizable approach for fine-tuning supramolecular chirality, which could be applied in developing treatments to regulate amyloid morphology in neurodegeneration and other disease states. The study highlights the importance of supramolecular chirality in biological systems, where helical structures with defined left- or right-handed twists guide function and dysfunction. These structures are stabilized by weak interactions and can undergo chiral conversion to achieve specific biofunctionality. The research shows that the chirality of amyloid assemblies can be influenced by sequence variations, with the KLVFFAE sequence forming left-handed supramolecular nanotubes, while substitutions like KLVFFAV lead to right-handed structures. The study also demonstrates that the chirality of β-sheets can be controlled through sequence modifications, with the C-terminal amino acid playing a critical role in determining the handedness of the structure. The study further explores the use of C-terminal modifications to tune the energy barrier for chirality inversion, enabling temperature-triggered chiral inversion of peptides to control drug release. The research shows that the ability to tune the chirality of amyloid-derived peptides through C-terminal modifications can enhance understanding of protein amyloidosis and provide insights for treating neurodegenerative diseases through manipulation of their chirality. The findings also suggest potential applications in synthetic materials and devices operating through chiral inversion. The study demonstrates that the chirality inversion of amyloid structures can be used to control the release of anticancer drugs, with the PEG2 derivative showing efficient drug release upon temperature-induced chirality inversion. The results highlight the potential of these materials for drug delivery, where the chirality inversion can be used to trigger drug release in response to temperature changes. The study also shows that the viability of cells treated with these materials is significantly reduced, indicating the effectiveness of the drug delivery system. Overall, the study provides insights into the sequence-specific regulation of supramolecular chirality in amyloid assemblies and its potential applications in designing tunable biomaterials for drug delivery and other biomedical applications. The findings suggest that the ability to control the chirality of amyloid structures through sequence modifications could lead to new approaches for treating neurodegenerative diseases and other conditions involving amyloid pathology.This study investigates the sequence-specific regulation of supramolecular chirality in amyloid-β42 (Aβ42) and its implications for designing tunable biomaterials. The research reveals that the central core of Aβ42, specifically the KLVFFAE sequence, exhibits sequence-specific chirality, with modifications at the C-terminus enabling chirality inversion at biologically relevant temperatures. The study demonstrates that C-terminal modifications can tune the energy barrier for left-to-right chiral inversion, allowing temperature-triggered chiral inversion of peptides hosting therapeutic payloads to modulate drug release. These findings suggest a generalizable approach for fine-tuning supramolecular chirality, which could be applied in developing treatments to regulate amyloid morphology in neurodegeneration and other disease states. The study highlights the importance of supramolecular chirality in biological systems, where helical structures with defined left- or right-handed twists guide function and dysfunction. These structures are stabilized by weak interactions and can undergo chiral conversion to achieve specific biofunctionality. The research shows that the chirality of amyloid assemblies can be influenced by sequence variations, with the KLVFFAE sequence forming left-handed supramolecular nanotubes, while substitutions like KLVFFAV lead to right-handed structures. The study also demonstrates that the chirality of β-sheets can be controlled through sequence modifications, with the C-terminal amino acid playing a critical role in determining the handedness of the structure. The study further explores the use of C-terminal modifications to tune the energy barrier for chirality inversion, enabling temperature-triggered chiral inversion of peptides to control drug release. The research shows that the ability to tune the chirality of amyloid-derived peptides through C-terminal modifications can enhance understanding of protein amyloidosis and provide insights for treating neurodegenerative diseases through manipulation of their chirality. The findings also suggest potential applications in synthetic materials and devices operating through chiral inversion. The study demonstrates that the chirality inversion of amyloid structures can be used to control the release of anticancer drugs, with the PEG2 derivative showing efficient drug release upon temperature-induced chirality inversion. The results highlight the potential of these materials for drug delivery, where the chirality inversion can be used to trigger drug release in response to temperature changes. The study also shows that the viability of cells treated with these materials is significantly reduced, indicating the effectiveness of the drug delivery system. Overall, the study provides insights into the sequence-specific regulation of supramolecular chirality in amyloid assemblies and its potential applications in designing tunable biomaterials for drug delivery and other biomedical applications. The findings suggest that the ability to control the chirality of amyloid structures through sequence modifications could lead to new approaches for treating neurodegenerative diseases and other conditions involving amyloid pathology.