Remodeling tumor microenvironment by versatile nanoplatform orchestrated mechanotherapy with chemoimmunotherapy to synergistically enhance anticancer efficiency.

Solid tumors (particularly the desmoplastic ones) usually harbor insurmountable mechanical barriers and formidable immunosuppressive tumor microenvironment (TME), which severely restricted nanomedicine-penetration and vastly crippled outcomes of numerous therapies. To overcome these barriers, a versatile nanoplatform orchestrated mechanotherapy with chemoimmunotherapy was developed here to simultaneously modulate tumor physical barriers and remodel TME for synergistically enhancing anticancer efficiency. Dexamethasone (DMS) and cis-aconityl-doxorubicin (CAD) were co-hitchhiked into phenylboronic acid functionalized polyethylenimine (PEI-PBA) carrier, and further in situ shielded by aldehyde-modified polyethylene glycol (PEG) to form CAD/DMS@PEG/PEI-PBA (CD@PB) nanoparticles (NPs). The CD@PB NPs exhibited multifunctionality: (1) Long in vivo circulation and acidic TME-responsive PEG deshielding for being efficiently internalized into cells. (2) Endosomal-pH triggered drug release and PEI-facilitated drug-escaping from endosome into cytoplasm. (3) DMS down-regulated thick stroma and weakened mechanical barriers for facilitating NP penetration. (4) DMS mediated nuclear pore dilation to promote more DOX entering nucleus and enhance treatment effects. (5) DOX induced potent immunogenic cell death (ICD), activated antitumor immunity and exerted chemoimmunotherapy. The versatile CD@PB NPs displayed excellent antitumor efficacy against 4T1 mouse breast cancer, which effectively remodeled immunosuppressive TME and orchestrated mechanotherapy with chemoimmunotherapy to synergistically enhance antitumor efficiency. The study provided an illuminating paradigm for multidimensional cancer therapy.