As an emerging and promising treatment method, gas therapy has attracted more and more attention for the treatment of inflammation-related diseases, especially cancer. However, therapeutic/therapy-assisted gases (NO, CO, H2S, H2, O2, SO2, and CO2) and most of their prodrugs lack the abilities of active intratumoral accumulation and controlled gas release, causing limited cancer therapy efficacy and potential side effects. Therefore, the development of nanomedicines to realize the tumour-targeted and controlled release of therapeutic/therapy-assisted gases is greatly desired, and also the combination of other therapeutic modes with gas therapy by multifunctional nanocarrier platforms can augment cancer therapy efficacy and also reduce their side effects. How to design nanomedicines with these functions is vitally important but challenging. In this review, we have summarized a series of engineering strategies for the construction of advanced gas-releasing nanomedicines from four aspects, 1) stimuli-responsive strategies for controlled gas release, 2) catalytic strategies for controlled gas release, 3) tumour-targeted gas delivery strategies, 4) multi-model combination strategies based on gas therapy. Moreover, we have also pointed out current issues and gaps in knowledge, and have envisaged current trends and future prospects of advanced nanomedicines for gas therapy of cancer. The review should be inspiring for guidance of the engineering of advanced gas-releasing nanomedicines.

There is a pressing need to develop nanoplatforms that integrate multimodal therapeutics to improve treatment responses and prolong the survival of patients with unresectable hepatocellular carcinoma (HCC). Mesoporous silica-coated gold nanomaterials have emerged as a novel multifunctional platform combining tunable surface plasmon resonance and mesoporous properties that exhibit multimodality properties in cancer theranostics. However, their reduced radiation-absorption efficiency and limited surface area hinder their further radiochemotherapeutic applications. To address these issues, we designed Janus-structured gold-mesoporous silica nanoparticles using a modified sol-gel method. This multifunctional theranostic nanoplatform was subsequently modified via the conjugation of folic acid for enhanced HCC targeting and internalization. The loaded anticancer agent doxorubicin can be released from the mesopores in a pH-responsive manner, facilitating selective and safe chemotherapy. Additionally, the combination of chemotherapy and radiotherapy induced synergistic anticancer effects in vitro and exhibited remarkable inhibition of tumor growth in vivo along with significantly reduced systematic toxicity. Additionally, the Janus NPs acted as targeted computed tomography (CT)-imaging agents for HCC diagnosis. Given their better performance in chemoradiotherapy and CT imaging as compared with that of their core-shell counterparts, this new nanoplatform designed with dual functionalities provides a promising strategy for unresectable HCC theranostics.

Drug therapy unavoidably brings toxic side effects and drug content-limited therapeutic efficacy although many nanocarriers have been developed to improve them to a certain extent. In this work, a concept of drug-free therapeutics is proposed and defined as a therapeutic methodology without the use of traditional toxic drugs, without the consumption of therapeutic agents during treatment but with the inexhaustible therapeutic capability to maximize the benefit of treatment, and a Z-scheme SnS1.68-WO2.41 nanocatalyst is developed to achieve near infrared (NIR)-photocatalytic generation of oxidative holes and hydrogen molecules for realizing combined hole/hydrogen therapy by the drug-free therapeutic strategy. Without the need of any drug and other therapeutic agent assistance, the nanocatalyst oxidizes/consumes intratumoral over-expressed glutathione (GSH) by holes and simultaneously generates hydrogen molecules in a lasting and controllable way under NIR irradiation. Mechanistically, generated hydrogen molecules and GSH consumption inhibit cancer cell energy and destroy intratumoral redox balance, respectively, to synergistically damage DNA and induce tumor cell apoptosis. High efficacy and biosafety of combined hole/hydrogen therapy of tumors are achieved by the nanocatalyst. The proposed catalysis-based drug-free therapeutic strategy breaks a pathway to realize high efficacy and low toxicity of cancer treatment.

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