Strategies for engineering advanced nanomedicines for gas therapy of cancer

As an emerging and promising treatment method, gas therapy has attracted more and more attention for 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, resulting in limited cancer therapy efficacy and potential side effects. Therefore, development of nanomedicines to realize tumor-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. The design of nanomedicines with these functions is vitally important, but challenging. In this review, we summarize a series of engineering strategies for 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) tumor-targeted gas delivery strategies; (4) multi-model combination strategies based on gas therapy. Moreover, we highlight current issues and gaps in knowledge, and envisage current trends and future prospects of advanced nanomedicines for gas therapy of cancer. This review aims to inspire and guide the engineering of advanced gas-releasing nanomedicines.