Laser-activatable oxygen self-supplying nanoplatform for efficiently overcoming colorectal cancer resistance by enhanced ferroptosis and alleviated hypoxic microenvironment

(2023) 27:92 Jiang et al. Biomaterials Research https://doi.org/10.1186/s40824-023-00427-1 RESEARCH ARTICLE Biomaterials Research Open Access Laser‑activatable oxygen self‑supplying nanoplatform for efficiently overcoming colorectal cancer resistance by enhanced ferroptosis and alleviated hypoxic microenvironment Hao Jiang1†, Hailong Tian2†, Zhihan Wang2†, Bowen Li2, Rui Chen1, Kangjia Luo1, Shuaijun Lu1, Edouard C. Nice3, Wei Zhang2, Canhua Huang1,2, Yuping Zhou1*, Shaojiang Zheng4* and Feng Gao1* Abstract Background Colorectal cancer (CRC) is the second most deadly cancer worldwide, with chemo-resistance remaining a major obstacle in CRC treatment. Notably, the imbalance of redox homeostasis-mediated ferroptosis and the modulation of hypoxic tumor microenvironment are regarded as new entry points for overcoming the chemo-resistance of CRC. Methods Inspired by this, we rationally designed a light-activatable oxygen self-supplying chemo-photothermal nanoplatform by co-assembling cisplatin (CDDP) and linoleic acid (LA)-tailored IR820 via enhanced ferroptosis against colorectal cancer chemo-resistance. In this nanoplatform, CDDP can produce hydrogen peroxide in CRC cells through a series of enzymatic reactions and subsequently release oxygen under laser-triggered photothermal to alleviate hypoxia. Additionally, the introduced LA can add exogenous unsaturated fatty acids into CRC cells, triggering ferroptosis via oxidative stress-related peroxidized lipid accumulation. Meanwhile, photothermal can efficiently boost the rate of enzymatic response and local blood flow, hence increasing the oxygen supply and oxidizing LA for enhanced ferroptosis. Results This nanoplatform exhibited excellent anti-tumor efficacy in chemo-resistant cell lines and showed potent inhibitory capability in nude mice xenograft models. Conclusions Taken together, this nanoplatform provides a promising paradigm via enhanced ferroptosis and alleviated hypoxia tumor microenvironment against CRC chemo-resistance. Keywords Colorectal cancer, Chemo-resistance, Ferroptosis, Chemo-photothermal therapy, Hypoxia † Hao Jiang, Hailong Tian and Zhihan Wang contributed equally to this work. *Correspondence: Yuping Zhou Shaojiang Zheng Feng Gao Full list of author information is available at the end of the article © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Jiang et al. Biomaterials Research (2023) 27:92 Page 2 of 20 Graphical Abstract Introduction Colorectal cancer (CRC) is one of the most common malignant tumors that seriously endanger human health because of its low cure rate [1]. Moreover, chemotherapy resistance is one of the main causes of recurrence in CRC patients and leads to poor prognosis. Emerging evidence has demonstrated that the hypoxic microenvironment commonly exists in solid tumors, and is tightly associated with cancer progression and resistance to therapy [2]. Particularly, large amounts of oxygen are consumed during the generation of drug-induced reactive oxygen species (ROS), which frequently leads to a poor response to pro-oxidative stress therapy. Therefore, relieving CRC tumor hypoxia is expected to be an effective way to enhance the anti-tumor effect and reverse resistance to pro-oxidative therapeutic agents [3]. Notably, another key pathophysiological feature of drug-resistant cancer cells that might be exploited is that they live in redox homeostasis, which is dynamically balanced at a level much higher than drug-sensitive cancer cells. Cellular redox homeostasis, a dynamic balance between the generation and elimination of ROS, is fundamentally important for maintaining a physiological steady state within a living cell. Unsurprisingly, drug-resistant cells have been shown to have high levels of antioxidant enzymes and other factors responsible, such as superoxide dismutase (SOD) and glutathione (GSH), for the production of antioxidants, which corresponds to chemotherapy resistance [4]. Consequently, drug-resistant cancer cells may be more susceptible to changing ROS levels, and utilizing this vulnerability to enhance chemotherapeutic response is expected. It should be noted that ferroptosis, a novel form of cell death associated with oxidative stress, can be used as an alternative pathway to overcome the resistance of conventional chemotherapy. Several studies have explored the manipulation of redox homeostasis in cancer cells by releasing Fe ions from nanoparticles to trigger ferroptosis. In these studies, stimuli-responsive nanoparticles were designed to release Fe ions into the tumor microenvironment, thereby disrupting redox balance and inducing ferroptosis [5–7]. On the other hand, under oxidative stress conditions, aberrant lipid metabolism can lead to lipid peroxidation and trigger ferroptosis, representing a novel mechanism of oxidative-mediated cell death [8]. These findings collectively underscore the significance of redox homeostasis manipulation for cancer therapy and pave the way for the development of novel nanoplatforms with enhanced therapeutic efficacy. Inspired by this, we subtly designed a light-activatable oxygen self-supplying chemo-photothermal nanoplatform (C820, Scheme 1) by co-assembling first-line chemotherapeutics cisplatin (CDDP) and linoleic acid (LA)-tailored photothermal agent IR820. Light Jiang et al. Biomaterials Research (2023) 27:92 Page 3 of 20 Scheme 1 a Preparation of C820 NPs. b Schematic illustration of the underlying mechanism of C820 NPs for enhancing CDDP-IR820 photochemotherapy sensitivity stimuli-responsive remote control is a method for manipulating specific events, processes, or functionalities within a biological system. It offers non-invasiveness, controllability, non-toxicity, and high spatiotemporal resolution [9–11]. We meticulously engineered the C820 nanoparticles as a chemo-photothermal nanoplatform, incorporating cisplatin (CDDP), linoleic acid (LA), and the photothermal agent IR820. The es (...truncated)