Introduction

Chemotherapy is one of the most common treatment strategies in the clinic for cancer, which however often has the issues of low therapeutic efficacy, intrinsic drug resistance and severe side effects [1,2,3]. Although nanomaterial-based drug delivery systems (DDSs) can mitigate the problems [4,5,6,7], ineluctable accumulation of therapeutic drugs in healthy tissues is still prominent. In contrast, stimuli-responsive DDSs with controllable on-demand drug release profiles have been demonstrated to allow highly specific cancer treatment with reduced toxic concerns to normal tissues [8,9,10]. Within the exciting stimuli-responsive DDSs, typical controlled release of drugs mainly relies on some endogenous reactions in the biological systems, such as, cleavages of reactive oxygen species (ROS)-responsive moieties by oxidative stress [33]. Although there are various light-sensitive moieties that are responsive to ultraviolet (UV)–visible light, their applications in DDSs are restricted by the high phototoxicity of UV light and shallow tissue penetration depths for both UV and visible lights (< 1 mm) [34,35,36]. In contrast, near-infrared (NIR) light (650–950 nm) displays negligible phototoxicity and can penetrate more deeply into biological tissues (1–3.5 mm) [37]. In the presence of suitable optical materials as the transducers, NIR light can be converted into heat for photothermal therapy (PTT), ROS for photodynamic therapy (PDT), and UV/visible photons for photoregulation [38,39,40]. Therefore, it is feasible to integrate thermal-, ROS- and short-wavelength light-sensitive components into DDSs to achieve photoresponsive drug release for precise cancer therapy.

Herein, we summarize the recent development of NIR photoresponsive DDSs with on-demand drug release profiles for cancer photo-chemotherapy. They are first classified into (i) photothermal responsive DDSs, (ii) photodynamic responsive DDSs, and (iii) photoconversion responsive DDSs based on three different photoresponsive mechanisms. The constructions, NIR light triggered drug release profiles of these DDSs, and their applications for cancer therapy are then introduced. At last, a brief conclusion and discussion of the existing challenges and further perspectives are given.

Classification of photoresponsive DDSs

NIR photoresponsive DDSs can be classified into three categories: (i) photothermal responsive DDSs, (ii) photodynamic responsive DDSs, and (iii) photoconversion responsive DDSs according to different mechanisms. For cancer therapy, DDSs are typically administered via intravenous injection, and accumulate into tumor tissues though the enhanced permeability and retention (EPR) effect [41]. The representative NIR photoresponsive DDSs used for synergetic treatments of tumors in living animals are listed in Table 1.

Table 1 Summary of representative NIR photoresponsive DDSs for cancer therapy
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Photothermal responsive DDSs achieve on-demand release of drugs via nanomaterial-mediated PTT under NIR laser irradiation to generate heat to destroy thermal-responsive materials (Fig. 1) [42]. Such a class of DDSs are generally constructed via integrating thermal-responsive components into nanomaterials containing drugs and photothermal agents [43, 44]. Due to the excellent photothermal conversion efficacy, NIR-absorbing dyes, polydopamine, Prussian blue, carbon, copper sulfide (CuS), bismuth sulfide (Bi2S3), and gold (Au) nanoparticles have been widely utilized to fabricate photothermal responsive DDSs.

Fig. 1
figure 1

Schematic illustration of NIR photoresponsive DDSs

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Photodynamic responsive DDSs rely on photosensitizer-mediated PDT to allow NIR triggered drug release (Fig. 1) [45]. PDT utilizes photosensitizers and light irradiation to generate ROS to induce cancer cell death [46]. Meanwhile, the hypoxic condition of tumors will be aggravated due to the continuous consumption of oxygen molecules in PDT process [47]. In view of this, integrations of ROS- and hypoxia-sensitive moieties into DDSs enable the development of ROS- and hypoxia-responsive DDSs, respectively [31]. The common photosensitizers for PDT include tetraphenylchlorin (TPC), indocyanine green (ICG), Rose bengal (RB), chlorin e6 (Ce6), porphyrin, pheophorbide A (PhA), boron dipyrromethene (BODIPY), conjugated polymer (CP), and semiconducting polymer (SP). Among them, ICG has been approved by the US Food and Drug Administration (FDA) for the clinical diagnosis and phototherapy [31].

Photoconversion responsive DDSs are fabricated through integrating UV/visible light-sensitive components (such as 2-nitrobenzyl, spiropyran, coumarin, 7-nitroindoli, donor–acceptor Stenhouse adduct, and azobenzene) into upconverting nanosystems with loadings or conjugations of drugs [68,69,70]. For example, Kim and Yong et al. constructed a mesoporous silica coated silver–gold hollow nanoplatform to precisely regulate the release of 5-fluorouracil (anticancer drug) for prostate cancer therapy and photothermal therapy [70]. The mesopores were capped with a thermosensitive PCM (lauric acid), which allowed for remote, precise, and spatiotemporal control of drug release via silver–gold nanoshell-mediated photothermal heating under NIR laser irradiation at 808 nm. Such a nanoplatform thus showed a synergistic effect in killing cancer cells. Since MSNs do not have photothermal effect, other photothermal agents are required to construct these MSN-based photothermal responsive DDSs.

Qian’s group developed a photothermal responsive DDS based on rod-based urchin-like Bi2S3 hollow nanoparticles (termed as U-BSHM) to allow precise release of chemotherapeutic agents for synergistic PTT/chemotherapy [71]. A sacrificial template engaged polyol route was used to synthesize U-BSHM as the photothermal agent with a photothermal conversion efficiency of 26.8%. U-BSHM was loaded with DOX and encapsulated with PCM of 1-tetradecanol (the melting point at around 38 °C) as the “gatekeeper” to form the photothermal responsive DDS (termed as PD@BS) (Fig. 4a). The release of DOX was rapidly increased upon NIR laser irradiation at 808 nm compared to that without laser irradiation (Fig. 4b). The cell viability of MDA-MB-231 cancer cells gradually decreased with the prolonged NIR laser irradiation time and elevated concentrations of DDSs, which was due to the synergetic action of PTT and released DOX induced by NIR laser irradiation. The temperature of MDA-MB-231 tumor regions of living mice after intratumoral injection of PD@BS gradually increased to a plateau of around 49 °C under NIR laser irradiation, which was enough to induce the release of DOX and ablate tumors. As a result, the therapeutic effect of PD@BS was obviously improved with NIR laser irradiation (Fig. 4c).

Fig. 4
figure 4

(Reproduced from Ref. [71] with permission from Elsevier, copyright 2020)

a Schematic illustration of thermosensitive urchin-like Bi2S3 hollow nanoparticles as photothermal responsive DDSs for photothermal-chemotherapy. b Cumulative release of DOX from PD@BS induced by cyclic “turn-on” and “turn-off” of NIR light at different times. c The growth curves of MDA-MB-231 tumors in different groups during a period of 12 days

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Several other photothermal agents have also been used to induce the phase changes of PCM to achieve on-demand releases of chemotherapeutic drugs and synergistic effects of PTT/chemotherapy. Cai and co-workers constructed a photothermal responsive DDS based on hollow magnetic Prussian blue nanoparticles for NIR light-triggered PTT/chemotherapy [72]. Such a DDS consisted of a Prussian blue coated hollow iron oxide magnetic nanoparticle as the carrier and photothermal agent, DOX as the chemotherapeutic drug, and a biocompatible PCM of 1-pentadecanol as the “drug-janitor” for controlled-release in response to increased temperature (> 42 °C). In such a system, the release of DOX from DDS was significantly increased upon 808 nm laser irradiation due to Prussian blue-mediated photothermal effect. After treatments, this system exerted synergistic PTT/chemotherapy and afforded an enhanced therapeutic efficacy in inhibiting the growth of human hepatoma HepG2 tumors compared to sole chemotherapy and PTT. Similarly, Guo’s group developed a mesoporous carbon nanoparticle (MCN)-based DDS filled with DOX and 1-tetradecano as the PCM in hollow cavities for NIR light-triggered release of DOX [73]. The cumulative DOX release was significantly increased under 808 nm laser irradiation via MCN-mediated photothermal effect. A much higher intracellular DOX level was observed in MCF-7/ADR cells after treatment with MCN-based DDS plus laser irradiation relative to those without laser irradiation. The apoptosis evaluation showed that the highest percentage of total apoptosis (49.7%) was caused by MCN-based DDS treatment plus NIR laser irradiation, which was 2.48-fold higher relative to that of free DOX treatment alone. This suggested an enhanced therapeutic effect induced by the NIR light-triggered PTT and drug release.

In addition to PTT/chemotherapy, photothermal responsive PCM-based hollow nanostructures have also been developed for synergistic PTT/PDT/chemotherapy. For example, hollow mesoporous ZrO2-coated Nd3+-doped UCNPs were used as the photothermal nanocarriers to load DOX, Ce6, and 1-tetradecanol (PCM), forming a DDS (termed as UCNPs@ZrO2-Ce6/DOX/PCM) [74]. Due to the UCNP-mediated PTT, the release efficiency upon 808 nm NIR laser irradiation reached 44.12%. The inhibitory effect of HeLa cancer cells after treatment of UCNPs@ZrO2-Ce6/DOX/PCM and laser irradiation reached nearly 100%, which was 3.2-, 2.3-, and 1.6-fold higher than that in sole PTT, free DOX and PTT + PDT group, respectively. An excellent in vivo synergistic antitumor efficacy was also verified in murine cervical U14 tumor-bearing mice after treatment with this nanosystem plus NIR laser irradiation. Similarly, Xu’s group constructed another photothermal responsive DDS (termed as HPDC) with a high photothermal conversion efficiency of 44.13% for synergistic PTT/PDT/chemotherapy [75]. Such a HPDC consisted of four key components: hollow mesoporous CuS nanoparticle as both the photothermal agent and nanocarrier, surface coated 1-tetradecanol as a PCM, DOX as a chemotherapy drug and Ce6 as a photodynamic photosensitizer. NIR laser irradiation at 808 nm increased local temperature via CuS-mediated PTT, which obviously increased the release of both DOX and Ce6. Their cumulative release reached 72.78 and 74.4% after six cycles of NIR laser irradiation, respectively, while only approximately 5% DOX or Ce6 in total was released without laser irradiation. Via HPDC-mediated synergistic PTT/PDT/chemotherapy, the growth of 4T1 tumors in living mice was almost completely inhibited, while other treatments failed to effectively suppress tumor growth.

This section summarizes the recent constructions of photothermal responsive liposomes and PCM-based hollow nanostructures for NIR photoactivated drug release through photothermal effect mediated phase transition of thermal-sensitive materials. The liposomes have intrinsic advantages of good biocompatibility and biodegradability, low toxicity and immunogenicity, tunable physicochemical and biophysical properties and unique capability of loading both lipophilic and hydrophilic drugs [76]. However, liposomes often exhibit low stability because the phospholipid can be easily oxidized and hydrolyzed. Moreover, the use of organic solvent or high temperature during the liposome fabrication process may affect the bioactivity of drug molecules [77]. The hollow nanostructure-based DDSs exhibit various advantages including excellent chemical stability, high drug loading capability, and abundant surface chemical groups for further functionalization [78,79,80]. However, they generally have the drawbacks of poor biodegradability and long-term toxic concerns in living bodies [81]. These disadvantages of photothermal responsive DDSs should be considered to facilitate their translation for clinical medicine.

Photodynamic responsive DDSs

In the typical process of PDT, photosensitizers not only convert light energy into ROS, but also deplete oxygen to increase the tumor hypoxia to a certain extent [47]. Hence, it is feasible to construct photodynamic responsive DDSs via integrating ROS- or hypoxia-cleavable moieties into DDSs.

ROS-responsive DDSs

ROS-responsive DDSs have been applied to selectively release various drugs into target tissues, which can be achieved via photo-controlled cleavage of ROS-responsive linkers [12, 82, 83]. For instance, Schnermann et al. reported the utilization of NIR light to cleave antibody–drug conjugates containing a cyanine photocage [84]. Such conjugates consisted of a heptamethine cyanine fluorophore serving as the photocaging component, combretastatin A4 (CA4) acting as the potent inhibitor of microtubule polymerization and a human epidermal growth factor receptor (EGFR)-binding monoclonal antibody. This linker strategy utilized carbamate functional groups as the antibody attachment points, which ensured the release of CA4 drugs from antibodies triggered by ROS generation form fluorophore under NIR laser irradiation at 690 nm. Moreover, the fluorescence signal of this system provided a useful marker to verify the accumulation of conjugates, while the loss of fluorescence signal after excitation by NIR light indicated drug release.

Another representative example of ROS-responsive DDS was demonstrated by Liu’ s group [85]. In this system, DOX was covalently conjugated to an organic conjugated polyelectrolyte (CPE) through a ROS-cleavable dithioketal linker. PEG chains and cRGD were also conjugated to the backbone of CPE to improve its solubility and target specificity to cancer cells, respectively. CPE was utilized as the photosensitizer to generate ROS upon white light irradiation, not only exerting PDT, but also triggering the cleavage of dithioketal linkers for on-demand DOX release, which permitted a synergistic cancer therapy with an enhanced therapeutic effect. The ROS-cleavable dithioketal linker was also utilized by **, light-harvesting unit integration, and incorporation of different optical materials have shown great potential in amplifying the photon conversion efficiencies [37]. Third, the in vivo long-term biocompatibility and biodegradability of NIR photoresponsive DDSs is questionable and the products of photoirradiation may cause some safety concerns. To address this issue, it is necessary to systemically evaluate their biosafety in living subjects. Alternatively, efforts can be made to enhance their biodegradability and/or reduce their dimensions for a rapid clearance via renal and/or hepatic excretions [121,122,123,124]. Fourth, the variety of photoresponsive components is very limited, and their manufactures require long processing time and high cost of production, which greatly hinders the large-scale manufacturing of photoresponsive DDSs for clinical and translational applications. Exploration of facile inexpensive manufacturing methodology and/or development of new photoresponsive components is desirable to achieve their clinical translation. At last, it is often difficult to identify the tumor regions and the optimal therapeutic windows for NIR laser irradiation. Additional imaging agents can be integrated into photoresponsive DDSs to realize imaging-guided cancer photo-chemotherapy.

In addition to anticancer drugs, NIR photoresponsive DDSs can be used for on-demand release of other agents to achieve different therapeutic purposes. For example, Chang’s group reported the use of Prussian blue nanocubes to mediate photothermic activation of a tumor suppressor gene (p53) for PTT-synergistic gene therapy of tumors [125]. Via integrating photoresponsive components with immunotherapeutic molecules into a single nanoplatform, it is probable to achieve photoactivation of cancer immunotherapy using NIR photoresponsive DDSs [45]. Furthermore, the feasibility of NIR photoresponsive DDSs for the treatments of diseases other than cancer such as neurodegenerative, cardiovascular, infectious, and autoimmune diseases can be explored. Overall, with the progression of extensive research that will enable a better understanding of the current state of art, NIR photoresponsive DDSs should be available for clinical applications in the near future.