Nano-drug delivery systems (NDDS) have gained widespread attention in the field of drug delivery and cancer therapy in recent years, primarily owing to their attributes, such as efficient drug encapsulation, prolonged circulation, and targeted drug delivery compared with traditional chemotherapeutic drugs (Da Silva et al., 2016, Dong et al., 2019, Liu et al., 2016, Ma et al., 2016, Torchilin, 2005). However, NDDS have not shown satisfactory therapeutic effects in clinical settings, which are mainly associated with limited drug delivery, especially to deep tumors. As a matter of fact, NDDS normally need to go through at least five steps during the delivery process after intravenous injection: blood circulation, accumulation and penetration in the tumor, cellular internalization, and intracellular drug release (Sun et al., 2017). NDDS with large sizes (normally around 100–200 nm) exhibited better accumulation at tumor sites relying on the enhanced permeation and retention (EPR) effect compared with the smaller ones (Qin et al., 2022). Nevertheless, due to the reduced transcapillary pressure gradient and elevated interstitial fluid pressure (IFP) caused by tumor abnormal vasculature and dysfunctional lymphatic drainage (Ju et al., 2014, Nia et al., 2020, Souri et al., 2022), large sizes of NDDS (>100 nm) are mainly distributed in the periphery of the tumors, but are difficult to penetrate into the deep tumor sites (Ikeda-Imafuku et al., 2022). NDDS with small particle sizes (especially below 30 nm) has been demonstrated to penetrate poorly permeable tumors. Therefore, to achieve effective accumulation near the tumor and further penetrate into the deep tumors, the development of size-tunable NDDS is in high demand to maximize the therapeutic effect against tumors. Additionally, reducing the premature release of the loaded drug during the systematic circulation but on-demand release drug at tumor sites is another challenge to enhance the anti-tumor effect (Sun et al., 2012).

Copolymers such as poly-acrylamide-co-acrylonitrile (p(AAm-co-AN)) which exhibit a sharp upper critical solution temperature (UCST) feature undergo the phase transition from the highly hydrophobic to hydrophilic form due to the break of hydrogen bonding within the core (Huang et al., 2019, Yang et al., 2018). Therefore, these polymers can easily self-assemble into micelles under UCST relying on the inter/intra-molecular hydrogen bonding and dissociate the structure into small micelles or even polymer chains above the UCST, which is expected to facilitate the release of loaded drugs. In this scenario, temperature elevation or heat is a prerequisite to trigger the structure alternation of these micelles. Exogenous stimulus especially light has exhibited its superiority as it is non-invasive and can be precisely controlled temporally and spatially. Near-infrared (NIR) light is a widely used light due to its favorable penetration depth in the tissues, and significantly reduced phototoxicity to normal tissues compared with ultraviolet light or visible light (Olejniczak et al., 2015, Yin et al., 2014). Under the irradiation of NIR light, photosensitizers can easily convert the light energy to heat, which simultaneously realize the photothermal therapy and trigger the dissociation of UCST-type polymeric micelles.

Gold nanoparticles (GNPs) (i.e. sphere, shell, rod, cage, flower, etc.) as a photosensitizer have aroused great attention in cancer theranostics not only due to their satisfactory biocompatibility but also their intriguing photothermal conversion ability and photothermal stability as well as their cancer diagnosis capability. GNPs with surface plasmon resonance (SPR) within the NIR region can efficiently convert absorbed NIR light to heat (Chen et al., 2016). NIR-absorbing GNPs normally require anisotropic morphology or rough surface to have a large NIR absorption cross-section (Nam et al., 2018). Among the anisotropic gold nanoparticles, gold nanoflowers (AuNFs) with multiple tips exhibited good photothermal conversion efficiency (Hasan et al., 2009, Hernandez Montoto et al., 2018, Wang et al., 2013, Zhu et al., 2020). Besides the photothermal effect, GNPs possess high atomic number and electron density, resulting in an efficient absorption of X-rays, which endow their imaging function to X-ray-based techniques (such as computed tomography (CT) (Chen et al., 2016). CT techniques clearly distinguish regions that can attenuate X-rays with great discrepancy (such as bones and soft tissues) but hardly differentiate soft tissues with similar attenuation characteristics (e.g. tumors and muscles) (Lipengolts et al., 2022). Compared with CT imaging, magnetic resonance imaging (MRI) shows high spatial resolution and sensitivity to soft tissues by reflecting the nuclear magnetic relaxation rate of protons (i.e. hydrogen) in different tissue environments, but cannot visualize regions with little hydrogen such as bones (Cui et al., 2018, Lipengolts et al., 2022). Therefore, the combination of CT and MRI which provide opposing imaging abilities can exhibit better diagnostic capabilities for oncology due to the unpredictability during the tumor growth process (Li et al., 2015, Perlman et al., 2019, Tian et al., 2015).

Herein, Magnetic iron oxide nanoparticles (Fe3O4 NPs) were selected as a contrast agent for MRI and their surfaces were decorated with gold nanoflowers (AuNFs) to enhance the CT imaging as well as serve as a photothermal agent. These magnetic-gold nanoflower composites (Fe3O4@AuNFs) were integrated into a UCST-type (p(AAm-co-AN)-PEG-LA) drug (doxorubicin, DOX)-loaded nanomicelles Fe3O4@AuNFs/DOX-M) for effective CT/MRI dual-modality imaging and combined photothermal and chemotherapy. After targeted accumulation of the micelles at the tumor periphery, exogenous NIR light was used to irradiate near the tumor sites, and the loaded Fe3O4@AuNFs converted the light to heat, which triggered the cleavage of the thermosensitive micelles into ultra-small micelles (∼5 nm). These ultra-small micelles could easily penetrate deep into the tumors and further release DOX, thus realizing the optimized synergistic therapy of tumors.