Cancer remains as a refractory disease worldwide and has received significant attention in the biomedical field [1], [2]. The traditional cancer treatment methods such as chemotherapy, surgery and radiotherapy face with the inability to completely eradicate tumor and toxic side effects. Hence, more efficient tumor treatment with high selectivity and safety need to be developed [3], [4]. In solid tumors, the tumor microenvironment (TME) typically exhibits distinctive physicochemical properties that differ from normal tissues, including acidic pH, severe hypoxia, overexpressed glutathione (GSH) and elevated hydrogen peroxide (H2O2), these physiological characteristics accelerate the proliferation and metastasis of malignant tumors [5], [6], [7]. Chemodynamic therapy (CDT), as a recently emerging therapeutic strategy has received great attention due to its high selectivity and minimal side effects [8], which utilizes various metal cations to convert endogenous H2O2 into hydroxyl radicals (•OH) through Fenton or Fenton-like reactions [9]. However, the efficiency of single CDT is often limited, attributed to the insufficient H2O2 content to generate enough highly toxic •OH and the strong scavenging effect of reactive oxygen species (ROS) by overexpressed GSH [10], [11]. Therefore, it is urgently needed to combine CDT with other therapeutic approaches to enhance the efficacy of cancer therapy.

Recently, phototherapy activated by external light sources is widely used in cancer therapy duo to its minimal invasiveness and high selectivity. Phototherapy includes photodynamic therapy (PDT) and photothermal therapy (PTT) [12], [13]. PDT could generate ROS through the electron/energy transfer of photosensitizers (PSs) under continuous irradiation by external light source, leading to tumor cell death [14]. PTT relies on photothermal transducing agents (PTAs) to convert light energy into local heat under near-infrared (NIR) light irradiation for tumor ablation, and the elevated local heat could further promote the generation of ROS in PDT and CDT [15], [16], [17]. Nonetheless, the heterogeneous distribution of photosensitive nanoplatform and the insufficient light penetration depth severely limited the phototherapy to completely eliminate cancer cells [18]. Therefore, the combination of phototherapy with CDT could be a more efficient strategy for tumor treatment by overcoming the limitations of monotherapy.

To design smart nanoplatforms for multimodal therapy, several organic and inorganic photo-responsive nanomaterials have been presented [19], [20], which could simultaneously induce PTT and PDT using a single-powered NIR light source, thereby improving the therapeutic efficiency, and reducing the cost and time of therapy [21]. However, the organic small molecules with the functions of PTT and PDT agent, such as indocyanine dyes, phthalocyanine and its derivatives, usually exhibit poor water solubility and photostability [22], [23]. In contrast, the inorganic nanomaterials with photo-responsive properties exhibit great advantages in construction of multifunctional nanoplatform due to their hydrophilicity and good biocompatibility [24]. For example, Yang et al. fabricated a novel Au nanocluster-Cu2+ based nanoplatform for cuproptosis enhanced PTT/PDT/CDT synergistic therapy through TME regulation [25]. Moreover, Ding et al. developed a multifunctional tungsten oxide (WO3-x)-based nanoplatform for PA imaging-guided synergistic PTT/PDT/CDT cancer therapy [26]. Although these inorganic nanoplatforms have made significant progress in PTT/PDT/CDT synergistic therapy, but the potential long-term toxicity caused by low clearance rate or very slow degradation rate in the body may severely limit their further clinical application [27], [28]. Furthermore, the size of nanoplatform is a crucial factor that impacts the effectiveness of tumor treatment. The nanoparticles with a size of 100–200 nm possess great accumulation capabilities in tumor site, but they are not conducive to tumor penetration [29]. On the other hand, nanoparticles with a diameter less than 10 nm could effectively penetrate deep into solid tumors, but they are easily filtered by the kidneys and then cleared through the urine [30]. Therefore, nanoplatform that could be decomposed into small-sized nanostructures after accumulated in the tumor site will be more beneficial for tumor penetration and cellular internalization [31]. Noteworthy, several biodegradable nanoplatforms that consist of MnO2 and CuS nanomaterials have been reported for multimodal cancer therapy [32], [33]. However, none of them considered the whole issues of long-term retention toxicity, biodegradability, tumor accumulation and penetration. Therefore, it is still challenging to rationally design a biosafe and size changeable nanoplatform that combines PTT, PDT, as well as CDT functions for synergistic tumor therapy.

Herein, we developed a TME-responsive size-changeable and biodegradable nanoplatform (HCMNs) through depositing CuS nanoparticles on amino-functionalized MnO2 nanosheets using a simple chemical co-precipitation method and further HA modification. The 2D-structured HCMNs possess high CuS deposition rate and thus exhibited excellent photothermal performance. The MnO2 nanosheets in the HCMNs could be rapidly degraded by GSH in the TME, and the released Mn2+ ions could not only effectively generate highly toxic •OH through the Fenton-like reaction to achieve CDT, but also enhance T1-weighted magnetic resonance (MR) imaging. Moreover, the CuS nanoparticles deposited in HCMNs could induce PTT and PDT under NIR irradiation, and the local heat in the PTT process further promote the production of ROS. Simultaneously, the ultra-small sized CuS nanoparticles from the decomposition of HCMNs are beneficial for tumor penetration, and could be slowly degraded in the TME after inducing PTT and PDT under NIR light irradiation. In addition, the HA modification could efficiently target the tumor cells, thereby improving the accumulation rate of HCMNs in the tumor site. Therefore, the prepared TME-responsive size-changeable and biodegradable HCMNs will be a promising nanoplatform for CDT/PTT/PDT synergistic therapy, which possess the great potential to improve the efficiency of tumor treatment and minimize the adverse side effects.