SIGNAL-Nano: a sequentially gated red light-activable silicon-rhodamine nanoplatform for mitochondria-targeted theranostics.
TL;DR
A sequentially gated theranostic nanoplatform based on a silicon-rhodamine (Si-Rhod) photocage that integrates endogenous reactive oxygen species sensitivity with externally applied red light activation to achieve spatiotemporally programmable chemotherapy is reported.
Abstract
Precise control over drug activation within heterogeneous tumor microenvironments remains a central challenge in the design of next-generation therapeutic materials. Here, we report a sequentially gated theranostic nanoplatform based on a silicon-rhodamine (Si-Rhod) photocage that integrates endogenous reactive oxygen species (ROS) sensitivity with externally applied red light (≥680 nm) activation to achieve spatiotemporally programmable chemotherapy. The molecular design enables a two-stage activation process, wherein ROS-mediated oxidation generates a fluorescent intermediate that subsequently undergoes efficient single-photon red light-triggered photolysis, releasing the active drug chlorambucil with high fidelity. The photocaged system self-assembles into nanoscale architectures, facilitating cellular uptake and enabling controlled intracellular delivery. Importantly, the Si-Rhod scaffold provides intrinsic mitochondrial targeting, introducing an additional level of subcellular precision in therapeutic activation. Photophysical and chromatographic analyses confirm rapid and near-quantitative photoconversion under biologically relevant conditions, while mechanistic studies reveal the cooperative interplay between oxidative activation and photochemical release. Functionally, the platform exhibits minimal dark toxicity but demonstrates pronounced light-triggered cytotoxicity across multiple biological models. In three-dimensional tumor spheroids, the system overcomes diffusion-limited drug penetration, achieving efficient activation within hypoxic tumor-like architectures. In vivo evaluation in a melanoma model further reveals significant tumor suppression under red light irradiation, accompanied by negligible systemic toxicity. This work establishes a generalizable design paradigm for sequentially gated theranostic materials, wherein endogenous biochemical cues are integrated with external photonic triggers to enable programmable, on-demand drug activation. The presented strategy advances silicon-rhodamine-based systems as a versatile platform for precision oncology and highlights their potential in the broader development of stimuli-responsive functional materials.
