Beta-Glucan Nanogels Mediate Intracellular Delivery of Elastin-Like Polypeptides for Efficient Macrophage Polarization.

Elastin-like polypeptides (ELPs) are promising drug delivery vehicles, yet their bioactivities remain underexplored, likely due to the lack of applicable protein delivery systems. To address this, here, a fusion protein ELP19 (19.5 kDa) and a β-glucan nanogel (for short, BGNG) system were designed and constructed. The BGNGs formed using dual phenylboronic acid (PBA)-functionalized poly(ethylene glycol) as a cross-linker through a reverse microemulsion method were utilized to individually load two different ELP variants (another ELP with a molecular weight of 17.035 kDa, termed as ELP17) for intracellular delivery and bioactivity investigation. The synthesized BGNGs with a size of 77.9 nm exhibit excellent protein-loading and delivery capabilities, and the developed BGNG/ELP complexes retain excellent colloidal stability and cytocompatibility. In vitro studies reveal that the BGNG-mediated intracellular delivery of ELP19 significantly promotes macrophage polarization toward the M2 phenotype, whereas the delivery of ELP17 shows no such effect. In addition, the BGNG/ELP19 complexes are able to maturate dendritic cells to generate immunogenicity, while BGNG/ELP17 complexes do not have such immunogenicity. These findings highlight the functional divergence between the two different ELP variants and underscore the potential of BGNGs as a protein carrier and ELP19 as a modulator of macrophages, providing a reference for the future biomedical application of BGNG-based nanoplatforms and ELP-based therapeutics.