Stimuli-responsive magnetic black phosphorus-based nanoreactor for chirality-dependent anoikis induction in cancer therapy

Abstract

Anoikis presents an alternative scheme for suppressing tumor metastasis. While limited by off-target effects, rapid degradation, and reactive oxygen species (ROS) accumulation, anoikis resistance remains a persistent challenge for current tumor therapy. The use of external and endogenous stimuli to trigger ROS bursts, as well as chirality-enhanced tumor microenvironment (TME) penetration, offers a valid solution. We developed a stimuli-responsive nanoreactor by coupling chiral histidine-modified manganese ferrite (MnFe 2 O 4 -PEG) nanoparticles with chiral cysteine-modified black phosphorus (BP) nanosheets via an ROS-sensitive thioketal (TK) bond to form a MnFe 2 O 4 -BP chiral magnetic nanoreactor (CT-MFBP). L-MFBP exhibited superior cellular uptake and intracellular retention due to its enhanced affinity for cell membranes. After entering the TME, the thioketal bond was cleaved by alternating magnetic field (AMF)-induced ROS, leading to the decomposition of the nanoreactor into chiral BP components. Subsequently, ROS accumulation was further amplified using BP-mediated photodynamic therapy (PDT). In addition, the nanoreactor demonstrated catalase (CAT)-like activity, converting endogenous H 2 O 2 into O 2 , thereby effectively alleviating the tumor hypoxic microenvironment and enhancing PDT efficacy. Furthermore, these events activated the mitogen-activated protein kinase (MAPK)-caspase 3 signaling pathway by upregulating p38 protein and Bcl-2-modifying factor (BMF) expression, which together promoted anoikis in tumor cells—a finding further validated by genomic analysis. Both in vitro and in vivo results confirmed that L-MFBP provides a robust regulatory strategy to induce anoikis and suppress tumor metastasis, offering a promising approach for chiral magnetic nanomedicine in clinical antitumor applications.