Hydrogen sulfide (H2S) as an important biological gasotransmitter plays a pivotal role in many physiological and pathological processes. The sensitive and quantitative detection of H2S level is therefore crucial for precise diagnosis and prognosis evaluation of various diseases but remains a huge challenge due to the lack of accurate and reliable analytical methods in vivo. In this work, we report a smart, H2S-responsive and depleting nanoplatform (ZNNPs) for quantitative and real-time imaging of endogenous H2S for early diagnosis and treatment of H2S-associated diseases. We show that ZNNPs exhibit unexpected NIR conversion (F1070 → F720) and ratiometric photoacoustic (PA680/PA900) signal responsiveness towards H2S, allowing for sensitive and quantitative visualization of H2S in acute hepatotoxicity, cerebral hemorrhage model as well as colorectal tumors in living mice. ZNNPs@FA simultaneously scavenges the mitochondrial H2S in tumors leading to significant ATP reduction and severe mitochondrial damage, together with the activated photodynamic effect, resulting in efficient suppression of colorectal tumor growth in mice. We believe that this platform may provide a powerful tool for studying the vital impacts of H2S in related diseases.

Developing endogenous photo‐activated theranostic platforms to overcome the limitation of low tissue‐penetration from external light sources is highly significant for cancer diagnosis and treatment. We report a H2O2‐initiated chemiluminescence (CL)‐triggered nanoparticle aggregation strategy to activate theranostic functions of gold nanoparticles (AuNPs) for effective tumor imaging and therapy. Two types of AuNPs (tAuNP & mAuNP) were designed and fabricated by conjugating 2,5‐diphenyltetrazole and methacrylic acid onto the surface of AuNPs, respectively. Luminol was adsorbed onto the mAuNPs to afford self‐illuminating mAuNP/Lu NPs that could produce strong CL by reaction with H2O2 in the tumor microenvironment, which triggers significant aggregation of AuNPs resulting in enhanced accumulation and retention of AuNPs for activated photoacoustic imaging and photothermal therapy of tumors. We thus believe that this approach may offer a promising tool for effective tumor treatment.

Tumor microenvironment plays a pivotal role in the growth and metastasis of tumors, and has become a promising target for precise diagnosis and treatment of tumors. Herein, a novel smart NIR theranostic probe Cy-1 that can simultaneously respond to low intracellular pH and reductive glutathione (GSH) is reported. This probe has demonstrated to be able to intermolecularly undergo a biologically compatible CBT-Cys condensation reaction to selectively form large nanoaggregates in the tumor microenvironment resulting in its enhanced accumulation and retention in the tumor, which as a consequence significantly improves the sensitivity of NIR/photoacoustic imaging and photothermal therapeutic efficacy of tumors in living mice. We thus believe that this dual stimuli-mediated self-assembly strategy may offer a promising and universal platform for cancer theranostics.

RNA interference (RNAi) has proved to be a promising modality for disease treatment. However, the promise of conventional RNA therapeutics for clinical application is severely impeded by low delivery efficiency and susceptibility of RNAs to serum RNases. Therefore, developing advanced RNAi technology is an increasing demand for achieving precise medicine. Herein, for the first time, we propose an alkaline phosphatase (ALP)-controllable and red light-activated RNA modification (ALARM) approach for anti-tumor therapeutic application. An ALP-responsive NIR fluorogenic probe f-RCP consisting of a tumor-targeting cyclic RGD peptide, an ALP-activated photosensitizer CyOP, and an 1O2-susceptible furan module for RNA modification was rationally designed and synthesized. Studies have demonstrated that f-RCP can specifically target to liver carcinoma HepG2 cells and spontaneously emit activated NIR/photoacoustic signals upon cleavage by the ALP enzyme, allowing for sensitive detection of ALP-positive tumors. More notably, we surprisingly found that the capability of f-RCP producing singlet oxygen (1O2) under red light irradiation could be simultaneously unlocked, which can ignite the covalent cyclization reaction between furan and nucleobases of intracellular RNA molecules, leading to significant mitochondrial damage and severe apoptosis of tumor cells, in consequence realizing efficient tumor suppression. Most importantly, the potential therapeutic mechanism was first explored on the transcriptomic level. This delicate ALARM strategy may open up new insights into cancer gene therapy.

Improving the enrichment of drugs or theranostic agents within tumors is very vital to achieve effective cancer diagnosis and therapy while greatly reducing the dosage and damage to normal tissues. Herein, as a proof of concept, we for the first time report a red light-initiated probe-RNA cross-linking (RLIPRC) strategy that can not only robustly promote the accumulation and retention of the probe in the tumor for prolonged imaging but also significantly inhibits the tumor growth. A near-infrared (NIR) fluorescent probe f-CR consisting of a NIR dye (Cyanine 7) as a signal reporter, a cyclic-(arginine-glycine-aspartic acid) (cRGD) peptide for tumor targeting, and a singlet oxygen (1O2)-sensitive furan moiety for RNA cross-linking was rationally designed and synthesized. This probe possessed both passive and active tumor targeting abilities and emitted intense NIR/photoacoustic (PA) signals, allowing for specific and sensitive dual-modality imaging of tumors in vivo. Notably, probe f-CR could be specifically and covalently cross-linked to cytoplasmic RNAs via the cycloaddition reaction between furan and adenine, cytosine, or guanine under the oxidation of 1O2 generated in situ by irradiation of methylene blue (MB) with 660 nm laser light, which effectively blocks the exocytosis of the probes resulting in enhanced tumor accumulation and retention. More excitingly, for the first time, we revealed that the covalent cross-linking of probe f-CR to cytoplasmic RNAs could induce severe apoptosis of cancer cells leading to remarkable tumor suppression. This study thus represents the first red light-initiated RNA cross-linking system with high potential to improve the diagnostic and therapeutic outcomes of tumors in vivo.