A novel silkworm excrement-derived nanomedicine integrating ferroptosis and photodynamic therapy, well-suitable for PD-L1-mediated immune checkpoint blockade

Abstract

The inherent tumor immunosuppressive microenvironment (TIME) of most solid tumors adversely affect the antitumor efficacy of immune checkpoint blockade (ICB) therapy, which is an urgent issue to be solved in clinical cancer therapy. In this study, a novel red-emitting carbon dots (SCDs) with photodynamic therapy (PDT) function was prepared for the first time using silkworm excrement, a biological waste. Additionally, an original tumor-targeted nano-micelle (HA-Fc) was first developed by conjugating hyaluronic acid (HA) to ferrocene (Fc) via the acid-sensitive Schiff base, which were then used to encapsulate Cu-doped SCDs to obtain HF-SCDs@Cu. HF-SCDs@Cu exhibited the pronounced targeting propensity to tumor tissue and degraded to release ferrocene, Cu²⁺, and SCDs under the specific acidic tumor microenvironment, thereby eliciting potent tumor immunogenic cell death function induced by ferroptosis and PDT. Moreover, the O₂-generating ability induced by HF-SCDs@Cu could reverse the hypoxic tumor microenvironment, enhancing the efficacy of PDT, and importantly, the expression of PD-L1 on tumor cell surfaces could be effectively downregulated by inhibiting the HIF-1α pathways, thereby augmenting the effect of anti-PD-L1 (αPD-L1) therapy. Therefore, this study presents a novel approach for the redevelopment of silkworm excrement and provides valuable strategies into enhancing PD-L1-mediated ICB therapy.