Cascade pH-responsive multi-drug delivery nanosystem actuates PANoptosis of triple-negative breast cancer

The efficient tumor ablation strategy accompanied with metastasis blocking is critical for triple-negative breast cancer (TNBC) therapy. Herein, we develop a cascade pH-responsive chemo-gene delivery nanosystem to actuate PANoptosis of tumor cells and suppress metastasis via bystander effect. Structurally, a charge reversal and acid-activated cell-penetrating peptide (CACPP) is covalently anchored onto GO surface, together with co-loading of doxorubicin (Dox) and TNBC-selective TRAIL expressing plasmid (pbTRAIL) onto GO surface via π-π stacking and calcium phosphate (CaP) biomineralization to yield nanosystem of Dox GPCaP pbTRAIL . After intravenous administration, the nanosystem could selectively accumulate at tumor site since CACPP modified nanosheet resurrects in tumor acidic microenvironment (Cascade 1). The internalized Dox GPCaP pbTRAIL nanosystem is further translocated into lysosome, where lower pH triggers burst drug release via Dox protonation and CaP dissolution (Cascade 2), followed with pbTRAIL liberation and lysosomal escape. The combination of Dox and TRAIL induces advanced apoptosis and necrosis of tumor cells; Meanwhile, GO-derived nanosheets share high photothermal conversion efficiency upon laser irradiation, thereby inducing pyroptosis and promoting PANoptosis synergistically. Our study demonstrates tumor-specific accumulation of Dox GPCaP pbTRAIL nanosystem and high capability of PANoptosis induction both in vitro and in vivo, yielding high tumor inhibition rate of 96 % and survival rate of 100 %. Collectively, the cascade pH-responsive multi-drug delivery nanosystem provides a novel approach for PANoptosis therapy of TNBC.