Fabrication of a Silk Sericin Hydrogel System Delivering Human Lactoferrin Using Genetically Engineered Silk with Improved Bioavailability to Alleviate Chemotherapy-Induced Immunosuppression

Abstract

Chemotherapy is one of the main treatments for cancer; however, it usually causes severe atrophy of immune organs and self-immunity damage to patients. Human lactoferrin (hLF) is a multiple biofunctional protein in regulating the immune response and thus holds great promise to alleviate chemotherapy-caused immunosuppression. However, a sufficient hLF resource and efficient delivery of hLF remain a challenge. Here, we provide a useful strategy to simultaneously solve these two problems. A silk sericin hydrogel system delivering recombinant hLF (SSH-rhLF) was fabricated to alleviate the chemotherapeutic drug-caused side effects by rhLF-carrying silk cocoons, which were cost-effectively produced by a transgenic silkworm strain as the resource. SSH-rhLF with a uniform porous microstructural morphology, a dominant β-sheet internal structure, adjustable concentration and sustainable release of the rhLF, and non-cytotoxicity properties was demonstrated. Interestingly, the sericin hydrogel showed effective protection of the rhLF from degradation in the stomach and small intestine, thus prolonging the bioactivity and bioavailability of rhLF. As a result, the oral administration of SSH-rhLF with a low rhLF dose showed significant therapeutic effects on enhancing the immune organs of cyclophosphamide (CTX)-treated mice by protecting the splenic follicles, promoting the expression of immunoregulatory factors, and recovering the intestinal flora family from CTX-induced imbalance, which were similar to those achieved by oral administration of a high dose of free hLF in the solution form. The results suggest that the strategy of producing rhLF silk cocoons via feeding transgenic silkworms overcomes well the shortage of rhLF resources, improves the bioavailability of oral rhLF, and alleviates the side effects of chemotherapeutic drugs on immune organs. The oral SSH-rhLF will be promising for applications in cancer chemotherapy and immunity enhancement of patients.

Waste to Wealth: Exploring the Versatile Prospects of Discarded Silk Sericin

“…The gel can be generated at lower temperatures and alkaline pH. The mechanical strength of sericin is improved by gelation as observed from different studies Various gel forms, including aerogels, hydrogels, and xerogels of sericin with various bio and synthetic polymers are being investigated by research groups for a wide range of end-use applications. − …”

Silkworm Cocoon: Dual Functions as a Traditional Chinese Medicine and the Raw Material of Promising Biocompatible Carriers

“…Therefore, it is considered not only to be a key component of traditional medicine but also a crucial material in contemporary medical innovation. Presently, its applications primarily manifest in areas such as drug delivery systems [24][25][26], tissue engineering [27][28][29][30], and regenerative medicine [30,31]. These studies leverage the biodegradability and excellent biocompatibility of SC to develop new medical materials and treatment methods, showcasing its potential as a natural resource in the contemporary medical domain.…”

Bioengineered silkworm model for expressing human neurotrophin-4 with potential biomedical application

“…Based on the silk gland-specific expression genes, sericin and fibroin promoters have been established to express exogenous proteins specifically localized in middle silk gland (MSG) and posterior silk gland (PSG), respectively, which has established the silkworm as an important host to express foreign proteins ( Kurihara et al, 2007 ; Tomita et al, 2007 ). Until now, most foreign proteins with various biological functions and potential biomedical applications have been successfully expressed in silk gland of silkworm, such as human lactoferrin, human platelet derived growth factor, human type III procollagen, human serum albumin, human acidic fibroblast growth factor, and others ( Tomita et al, 2003 ; Ogawa et al, 2007 ; Wang et al, 2015 ; Chen et al, 2018 ; Xu et al, 2021 ). Therefore, make the best of silk gland via transgenic silkworm has also been an ideal bioreactor for producing recombinant drug proteins in a large scale to meet the growing clinical needs and applications.…”