Construction Of Self-assembled Nanomedicines Based On Amino Acids And Short Peptides And Their Application In Tumor Treatmen

Nature constructs simple small biological molecules into biofunctional systems with complex structures in an exquisite self-assembly process.Inspired by bioassemblies,the self-assembly of small biological molecules offers new strategies for the construction of functional materials,especially nanomaterials with applications in tumor therapy.Tumor treatment remains one of the major challenges facing the world today.In view of the disadvantages of traditional chemotherapy such as high toxic side effects and susceptibility to multidrug resistance,emerging tools such as chemodynamic therapy and photothermal immunotherapy have attracted much attention in the field of precision anti-cancer because of their high targeting,low toxic side effects and lack of multidrug resistance.However,shortcomings in the core elements of these therapies,such as catalysts and photosensitizers,have limited their further clinical application and development.For example,traditional inorganic catalysts in chemokinetic therapy have low biosafety and a single tumor-specific response mode;photothermal agents in photothermal therapy have poor water solubility,short blood half-life and no absorption in the biologically transparent window（800-1000 nm）.Therefore,the key to solving these problems is how to construct nanomedicine with specific structures and functions through rational design and selection of biomolecules and flexible regulation of the molecular self-assembly process.Inspired by the structure of natural proteins,we propose to use simple amino acids and functional short peptides as substrates to modulate the self-assembly process to construct nano-catalysts with high catalytic activity and photothermal nanofibers with ultra-large red-shift through the synergy of weak intermolecular interactions to achieve effective tumor therapy by:（1）Inspired by natural horseradish peroxidase,amphiphilic Fmoc-serine（Fmoc-S）,Fe³⁺and the chemotherapeutic drug doxorubicin（DOX）were selected to construct metallo-nanoenzymes by simple multi-component coordination self-assembly.The prepared nanoenzymes are spherical nanostructures with a uniform particle size distribution of about 100 nm and a high doxorubicin loading of more than 70%.Most importantly,the nanoenzymes specifically consume high levels of glutathione in tumor cells and convert Fe³⁺to Fe²⁺,converting excess hydrogen peroxide in tumor cells to highly cytotoxic hydroxyl radicals in a peroxidase-like catalytic manner.At the same time,the nanoenzymes is activated in situ to release chemotherapeutic agents within the tumor cells for enhanced treatment.In vitro and in vivo evaluations have shown that supramolecular nanoenzymes significantly inhibit tumor growth through co-catalytic chemotherapy without any systemic toxicity.（2）Inspired by the regulation of pigment uptake by proteins in nature,functional short peptides were selected as assembly modules to regulate the kinetic self-assembly of phthalocyanines,and novel J-aggregate nanofibers with an absorption redshift greater than 150 nm were successfully obtained.The obtained supramolecular nanofibers exhibit extremely high absorption at 830 nm,with a photothermal conversion efficiency of 56.7%.The photothermal effect not only ablates cancer cells directly,but also induces immunogenic cell death in cancer cells,generating a series of signaling molecules such as calreticulin exposed on the cell surface and high mobility group protein B1 secreted to the extracellular compartment.By combining immunogenic cell death with the immune enhancing effect of thymopentin,the primary tumor can be effectively removed and the growth of distant tumors can be inhibited with minimal adverse effects.The construction of supramolecular metalloenzymes with high catalytic activity and photothermal nanofibers with ultra-large redshifts through the modulation of the self-assembly process enables effective chemotherapy-catalyzed treatment and photothermal immunotherapy.