Lu T.-YLu W.-FWang Y.-HLiao M.-YWei YFan Y.-JChuang E.-YYu J.JIASHING YU2022-03-222022-03-22202119448244https://www.scopus.com/inward/record.uri?eid=2-s2.0-85113780540&doi=10.1021%2facsami.1c10160&partnerID=40&md5=4cac2a18bcf17b12cf7aab471a2958d0https://scholars.lib.ntu.edu.tw/handle/123456789/598227Photodynamic therapy (PDT) holds tantalizing prospects of a prominent cancer treatment strategy. However, its efficacy remains limited by virtue of the hypoxic tumor microenvironment and the inadequate tumor-targeted delivery of photosensitizers, and these can be further exacerbated by the lack of development of a well-controlled nitric oxide (NO) release system at the target site. Inspired by Chinese medicine, we propose a revealing new keratin application. Keratin has garnered attention as an NO generator; however, its oncological use has rarely been investigated. We hypothesized that the incorporation of a phenylboronic acid (PBA) targeting ligand/methylene blue (MB) photosensitizer with a keratin NO donor would facilitate precise tumor delivery, enhancing PDT. Herein, we demonstrated that MB@keratin/PBA/d-α-tocopherol polyethylene glycol 1000 succinate (TPGS) nanoparticles (MB@KPTNPs) specifically targeted breast cancer cells and effectively suppressed their growth. Through MB-mediated biometabolism, the endocytic MB@KPTNPs produced a sufficient amount of intracellular NO that reduced the glutathione level while boosting the efficiency of PDT. A therapeutic combination of NO/PDT was therefore achieved, resulting in significant inhibition of both in vivo tumor growth and lung metastasis. These findings underscore the importance of utilizing keratin-based nanoparticles that simultaneously combine targeting of the tumor and self-generating NO with a cascading catalytic ability as a novel oxidation therapeutic strategy for enhancing PDT. ? 2021 American Chemical Society.biomass human hair keratinglutathione depletionnitric oxide generationphotodynamic therapyreactive nitrogen speciestumor targetingCatalytic oxidationDiseasesNanoparticlesNitric oxidePhotodynamic therapyPhotosensitizersTumorsBreast cancer cellsCatalytic capabilityPhenylboronic acidsPhotodynamic therapy (PDT)Targeting ligandsTherapeutic strategyTumor microenvironmentTumor targeted deliveryKeratinantineoplastic agentkeratinnanoparticlenitric oxideanimalBagg albino mousebreast tumorfemalehumanmousephotochemotherapyprocedurestumor cell lineAnimalsAntineoplastic AgentsBreast NeoplasmsCell Line, TumorFemaleHumansKeratinsMiceMice, Inbred BALB CNitric OxidePhotochemotherapy[SDGs]SDG3journal article10.1021/acsami.1c10160343517542-s2.0-85113780540