Smart stimulus-responsive mesoporous silicon combined with chemotherapy and photothermal therapy reverses tumor immunosuppressive microenvironment to enhances antitumor immunity

Abstract

Abstract Due to the tumor immunosuppressive microenvironment and potential systemic toxicity, chemotherapy often fails to trigger satisfactory anti-tumor results, so how to activate anti-tumor immunity to improve the therapeutic effect remains a challenging problem. Photothermal therapy (PTT) is an efficient method of inducing the tumor neoantigen release in situ, which offers potential for application in cancer immunotherapy. In this study, we constructed mesoporous silicon nanoparticles (MSNs) containing tetrasulfide bonds loaded with the traditional drug doxorubicin (DOX) inside and modified the outer layer with polydopamine (DOX/MSN-4S@PDA) for both in vivo and in vitro anti-tumor studies. Additionally, the mesoporous silicon core contains GSH-sensitive tetrasulfide bonds, which not only enhances the release of DOX but also generates hydrogen sulfide (H2S) which greatly improves the therapeutic effect of DOX. The polydopamine (PDA) in the outer layer provides the nanoparticles with acid sensitivity as well as a mild photothermal effect when exposed to near-infrared (NIR) light irradiation. Furthermore, the outermost layer is modified with hyaluronic acid (HA), allowing for targeted delivery to CD44-expressing tumor cells, further improving the accumulation of drugs at the tumor site and reducing toxic side effects. Results of our in vivo studies indicated that DOX/MSN@PDA-HA can reverse the immunosuppressive tumor microenvironment and improve the anti-tumor effect by triggering powerful immunogenic cell death (ICD) of tumor cells. Meanwhile, in vivo results showed that DOX/MSN@PDA-HA can significantly inhibit tumor metastasis to the lungs and liver. In summary, DOX/MSN@PDA-HA exhibits controlled release of therapeutic drugs, excellent biocompatibility, and significant tumor inhibition capabilities through synergistic chemical/photothermal combined therapy.