1 Introduction

1.1 Overview of photothermal therapy (PTT) as a cancer treatment strategy

Cancer is a global health problem that needs effective treatment strategies. It is the second leading cause of death in the United States where over 600,000 people are expected to die from cancer in 2022 [1]. Conventional treatments for solid-tumor cancers include surgical resection, radiotherapy, and chemotherapy, which are often used in combination. While surgery may work against early-stage disease, in most cases it fails to remove all cancer cells, leading to recurrence. Radiotherapy and chemotherapy also face limitations as both can unintentionally harm healthy tissues and encounter cancer cell resistance [2]. There is an urgent clinical need for potent and precise treatments that can destroy solid-tumor cancers while minimizing off-target effects.

Nanoparticle-mediated photothermal therapy (PTT) is a non-invasive treatment method with immense promise as a standalone or adjuvant therapy for solid-tumor cancers. In PTT, light-responsive nanoparticles (NPs) are intravenously (IV) administered and accumulate in the tumor site, which is then irradiated with an externally applied laser tuned to match the peak plasmon resonance/absorbance wavelength of the NPs. The light irradiation causes the NPs to produce heat that irreversibly damages cancer cells in the surrounding tumor tissue (Scheme 1A, B) [3]. Apart from killing the primary tumor, under the right conditions PTT can induce an anti-tumor immunological effect that can prevent or treat metastasis and/or reduce recurrence through the release of tumor-associated antigens by the ablated tumor cells [4]. A major benefit of PTT is its high precision, as thermal ablation is achieved only at the tumor site where NPs and light are combined. Hence, off-target effects are negligible. Excitingly, PTT mediated by silica core/gold shell “nanoshells” (also known as auroshells) has entered human clinical trials, with promising results reported [5,6,7]. Moreover, preclinical studies have shown that PTT can greatly enhance the efficacy of chemotherapy [8,9,10,11], radiotherapy [12,13,14] and immunotherapy [15, 34, 39, 99]. Several studies have shown that drug release from photothermally responsive membrane-wrapped NPs is both pH- and NIR light activation-dependent, allowing for high precision therapy [50, 64, 86]. Despite the good biocompatibility and biodegradability of organic liposomal and polymer-based NPs, they have inherent limitations compared to inorganic NPs including low photothermal conversion efficiency and poor photothermal stability under repeated laser irradiation [100]. Overall, the composition of the NP core is an important consideration for designing cell membrane-wrapped photothermal converters as it dictates their heating efficiency, stability, cargo-release kinetics, biocompatibility, and overall performance once the NP has been guided to the desired cancer cells by the membrane layer.

3 Membrane types used to wrap phototherapeutic NPs

Diverse cell types can be used as membrane sources to produce biomimetic NPs, with each membrane type offering unique features and capabilities that are derived from the specific proteins present in the bilayer structure (Scheme 2, Table 2). For example, RBC membrane coatings impart NPs with improved immune evasion owing to the presence of “self-markers” [68, 108]. Despite MSCs’ tumor homing abilities, safety in allogeneic transplantation, and variety of tissue sources, the actual number of MSCs recovered from tissues is small and the high cost of obtaining and maintaining these MSCs may limit the clinical translation of MSC membrane-wrapped NPs for PTT compared to other cell membrane sources [104].

Macrophages are an attractive membrane source for biomimetic NPs because these circulating sentinels have the ability to distinguish, phagocytose, and eliminate foreign materials and malignant cells, including cancer and inflammatory cells [52, 66]. Although the active targeting of macrophages to tumors is not strong towards all tumor types, the presence of α4 integrin on macrophage membranes allows for binding to cancer cells that overexpress vascular cell adhesion molecule-1 [52, 109]. This α4 integrin/VCAM-1 binding was exploited to promote the accumulation of macrophage membrane-wrapped NPs in MDA-MB-231 primary tumors and lung metastases in mice in a recent study [111]. Moreover, researchers should evaluate the pharmacodynamics and efficacy of membrane-wrapped NPs in preclinical studies to identify the dosing regimen that induces maximum therapeutic effect. For a more detailed discussion and guide on how to evaluate pharmacokinetics and pharmacodynamics, readers can refer to a previous review that discusses the best practices for preclinical in vivo testing of cancer nanomedicines [111]. The following section describes specific examples of membrane-wrapped NPs used for PTT alone or in combination with other treatment modalities (Scheme 3).

Scheme 3
scheme 3

Membrane-wrapped NPs are being developed to enable PTT alone and in combination with other treatment or imaging modalities to ensure complete ablation of primary tumors and metastatic lesions and provide lasting anti-tumor effects that prevent recurrence. Portions of this figure were produced using Servier Medical Art templates (https://smart.servier.com). Servier Medical Art by Servier is licensed under a Creative Commons Attribution 4.0 Unported License

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4 Membrane-wrapped NPs used for PTT in preclinical studies

4.1 Membrane-wrapped NPs for PTT as a standalone therapy

PTT mediated by membrane-wrapped NPs is rapidly develo** as a standalone therapy for solid-tumor cancers because it offers precise tumor ablation. Various kinds of NPs (e.g., nanoshells [44], nanorods [43], nanocages [44]. The mesoporous silica was loaded with Cy7 to enable in vivo fluorescence imaging, and the silica core-gold shell thickness ratio was tuned such that the peak SPR was near 800 nm. Coating the NPs with macrophage membranes slightly red-shifted the SPR peak and did not hinder the heat conversion properties; when diluted to 1 mg/mL in aqueous solution the NPs’ temperature increased  ~ 30 °C within 5 min of irradiation with an 808 nm laser at 1 W/cm2. The anti-tumor effect of this platform was tested in male BALB/c nude mice bearing 100 mm3 subcutaneous 4T1 murine breast tumors. Twenty minutes after saline, unwrapped NPs, or wrapped NPs were administered IV, the tumors were irradiated with an 808 nm laser at 1 W/cm2 for 5 min. Tumor growth was monitored over 25 days, during which only the mice treated with membrane-wrapped NPs and the laser experienced nearly complete tumor regression; all other treatment groups exhibited tumor growth. A biodistribution study showed that the macrophage membrane-wrapped NPs had longer circulation and  ~ 4.6X greater tumor accumulation than their unwrapped counterparts (7.48% injected dose per g (ID/g) in tumors for membrane-wrapped NPs versus 1.61% ID/g for unwrapped NPs), which likely contributed to their improved PTT effect [44].

In a similar study, Piao et al. functionalized photoresponsive gold nanocages (AuNCs) with poly(vinylpyrrolidone) (PVP, a biopolymer that is a potential alternative to PEG) and wrapped these PVP-AuNCs with RBC membranes [43]. In vivo, that platelet membrane-wrapped AuNRs (PLT-M-AuNRs) had similar, although slightly reduced, photothermal efficacy as AuNRs loaded within intact platelets (PLT-AuNRs). Specifically, PLT-AuNRs had longer blood circulation compared to PLT-M-AuNRs when administered IV to ICR mice. Additionally, the PLT-AuNRs exhibited improved tumor delivery when IV administered to mice bearing CAL27 head and neck squamous cell carcinoma tumor xenografts in the oral cavity. Accordingly, after the mice were irradiated with an 808 nm laser 24 h post-NP injection, tumor growth was slowest over the following 15 days in mice that received PLT-AuNRs plus laser, though the PLT-M-AuNRs plus laser also decreased tumor growth compared to AuNR plus laser. This study demonstrates that both membrane-wrap** of singular NPs and loading NPs within intact cells are promising approaches to enhance the efficacy of PTT versus traditional PTT mediated by non-biomimetic NPs.

Beyond gold-based NPs, other materials have been used to enable PTT including polymer-based NPs [85], mesoporous silica loaded with IR780 [73]. They developed ICG-loaded liposomes wrapped with C6 glioma cell membranes, which had peak absorption at  ~ 800 nm, close to that of the free dye at 780 nm, and which also exhibited prolonged blood circulation time and improved accumulation in subcutaneous C6 glioma tumors in BALB/c nude mice. The impact of PTT was examined by irradiating 60 mm3 tumors 1-h post-IV NP administration with an 808 nm laser at 1 W/cm2 for 5 min. Within 18 days, the primary tumor was completely eradicated in mice treated with the C6 membrane-wrapped liposomes, with no tumor relapse or formation of lung metastases observed. By comparison, neither free ICG nor unwrapped ICG-loaded liposomes completely eradicated tumors following irradiation, and some lung metastases were identified in these mice post-mortem. Given that metastasis is a leading cause of cancer death, future work should study the mechanism by which the homotypic PTT inhibited lung metastasis and increased antitumor immune response.

Other examples of membrane-wrapped NPs explored for PTT alone include colon cancer cell membrane-wrapped bismuth NPs (which support homotypic tumor targeting) [60], and macrophage membrane-wrapped magnetic iron oxide NPs (which support tumor delivery through both cell adhesion molecules present on the macrophage membranes and through NP attraction to an externally applied magnet) [69]. Another example includes halloysite nanotubes loaded with ICG which were coated with antibody-modified RBC membranes to target epithelial cell adhesion molecule (EpCAM) receptors that are overexpressed on breast cancer cells [89]. These examples and those discussed above demonstrate that a plethora of membrane-wrap** strategies can be utilized to enhance the success of PTT.

Across studies, membrane-wrapped NPs have outperformed their unwrapped counterparts, supporting continued development of membrane-wrapped NPs for PTT. Despite the success of these platforms to thermally ablate solid-tumor cancers under NIR irradiation, PTT as a standalone therapy has some limitations in the long term. For example, PTT can be ineffective if it fails to kill cancer cells in the primary tumor that are outside the irradiation region or if it fails to eliminate metastatic disease. To solve these issues, membrane-wrapped NPs have been developed that can both mediate PTT and provide contrast for various imaging modalities to ensure complete and precise ablation of the entire tumor [45, 49, 63] and black phosphorus nanosheets (that were coordinated with the active species of oxaliplatin (1,2-diaminocyclohexane) platinum (II) (DACHPt) as the chemotherapeutic and coated with MSC membranes) [40]. Primary tumors were irradiated (808 nm laser, 2.5 W/cm2, 5 min) every 3 days for four times after NP injection. Primary tumor volume was suppressed by 98.9% and lung metastases were dramatically decreased by 98.5%, demonstrating that biomimetic drug-loaded nanocages have great potential as anti-tumor and anti-metastasis agents. The impact of drug-loaded membrane-wrapped nanocages against 4T1 tumors in mice was also shown by Zhu et al. who loaded nanocages with PTX and wrapped the NPs with RBC membranes that were modified with anti-EPCAM (epithelial cell adhesion molecule) antibodies to allow the NPs to actively target EpCAM transmembrane proteins that are overexpressed in breast cancer [96]. Following in vitro studies that validated the improved uptake of membrane-wrapped SPNs versus uSPNs in activated fibroblast and 4T1 cell cultures, in vivo studies were performed wherein AF-SPNs and controls were IV administered to nude mice bearing 4T1 tumors. Forty-eight hours post injection, the tumor fluorescence intensity of AF-SPN treated mice was 1.5- and 1.3-fold higher than that of uSPN and CC-SPN injected mice, respectively. Correspondingly, the maximal PA intensity enhancement (ΔPA) in AF-SPN treated mice was 1.8- and 1.5-fold higher than that for uSPN and CC-SPN treated mice, respectively. To test phototherapeutic efficacy, mice were exposed to 808 nm laser irradiation (0.3 W/cm2 for 5 min) forty-eight hours post IV treatment administration. The maximal tumor temperature was 50 °C for AF-SPN injected mice, which was 4.0, 6.0, and 14.0 °C higher than that for CC-SPN, uSPN, and saline injected mice, respectively. Congruently, tumor volumes decreased to a greater extent in mice that received irradiation plus AF-SPN treatment compared to uSPN, CC-SPN, and saline controls. Post-mortem analysis of excised tumors confirmed that the tumor response was mediated by PDT in addition to PTT. Overall, this study confirmed that targeting activated fibroblasts with membrane-wrapped SPNs is a promising approach to enhance cancer imaging and phototherapy. In aggregate, the studies discussed in this section demonstrate that dual PTT/PDT mediated by membrane-wrapped NPs is a therapeutic approach with great potential against solid tumor cancers.

5 Conclusions: remaining challenges and the path forward for membrane-wrapped NPs for PTT

This review highlights the current state-of-the-art in cell-membrane camouflaged NPs for solid-tumor cancer PTT. Effective PTT requires photothermally-active NPs to accumulate at the tumor site in quantities that are sufficient to increase temperatures above 42 °C upon NIR irradiation to kill cancer cells [32]. One challenge is that photoresponsive NPs (like other nanomaterials and small drugs) are quickly recognized by the immune system as foreign invaders and are cleared from circulation, limiting tumor accumulation. Camouflaging photosensitive NPs with cell membranes does not alter their optical properties or heating abilities [44, 118]. To further increase tumor targeting, source cell membranes can be engineered to express tumor-targeting moieties or functionalized with antibodies or other ligands specific to receptors that are overexpressed on the target cancer cells [27, 119]. Such approaches remain to be refined and improved but have great promise.

Importantly, membrane-wrapped NPs for PTT must not only be effective in eliciting tumor heating above the damage threshold, but also have a reasonable safety profile such that their efficacy substantially outweighs any potential toxicity. It is hence imperative that researchers confirm both the NP core and the membrane coating are independently biocompatible. This biocompatibility can be assessed through histological methods, evaluation of serum cytokines and liver enzymes, hemolysis assays, complete blood count tests, as well as other techniques that are common in preclinical and clinical studies [111, 120, 121]. Current research indicates minimal toxicity of membrane-wrapped NPs, but thorough analysis will be required before these systems can move forward to human clinical testing and use.

Excitingly, membrane-wrapped NPs can enable not only PTT, but also stimuli-responsive release of encapsulated drugs or immunostimulatory agents to maximize tumor inhibition in combined treatment strategies [30]. PTT has been limited by the shallow penetration depth of laser light in tissues in vivo, making it ineffective in eradicating deep-tumors. Combining PTT with other therapies, or develo** photosensitizers that absorb light in the NIR-II window rather than the NIR-I window, can help overcome this limitation [32, 100]. This has been demonstrated as feasible in literature, where PTT has been combined with chemotherapy, PDT, immunotherapy, and RT with great success [41, 45, 84, 94]. Compared to PTT alone, which may effectively treat only primary tumors, studies have shown that membrane-wrapped NPs enabling PTT along with other therapies can inhibit primary tumors, metastases, and even prevent recurrence [68, 84, 94]. In particular, PTT + chemotherapy and PTT + immunotherapy are amenable to the treatment of metastatic disease [40, 9). This would allow membrane-wrapped NPs carrying distinct cargo to be tested in the chip to identify the best therapeutic approach (i.e., PTT applied alone or in combination with chemotherapy, immunotherapy, RT, or PDT) for a specific patient prior to administering the most effective mono or combination therapy in the clinic (Scheme 9). Such strategies are bold and challenging, yet also achievable given recent advancements in the field.

Scheme 9.
scheme 9

Scheme depicting a vision for the future development of personalized therapies based on phototherapeutic membrane-wrapped NPs. Individual patient’s own cancer cells (obtained from a biopsy) could be used to create both membrane-wrapped NPs and tumor-on-a-chip models that would be implemented to test the efficacy of PTT alone or in combination regimens. The most effective strategy identified in the model could then be administered to the patient. Portions of this figure were produced using Servier Medical Art templates (https://smart.servier.com). Servier Medical Art by Servier is licensed under a Creative Commons Attribution 4.0 Unported License

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Lastly, for cell membrane-wrapped phototherapeutic NPs to be successful clinically, manufacturing scale-up needs to be developed and optimized. The process of membrane extraction needs to be improved to minimize material loss [118]. Different membrane extraction and wrap** methods have been reported [34], but the parameters are varied and there is currently no basis for judgment on which method is better. Moreover, batch-to-batch consistency for multi-component biomimetic phototherapeutic NPs needs to be addressed before scaling up. Clinical doses of membrane-wrapped NPs will require huge amounts of membranes to be extracted (which is time-consuming and labor-intensive), and large volumes of NP cores will need to be produced. The process of fusing membrane vesicles with NPs will need to be optimized for large-scale production. Microfluidic electroporation devices may offer one strategy to commercialize the fusion process [62]. Finally, good manufacturing practices (GMPs) and good laboratory practices (GLPs) must be established to ensure quality standards are met and improve the rate of translating nanomedicine from bench to bedside.

Once the issues discussed here are addressed, PTT mediated by membrane-wrapped NPs will have great potential to transform cancer patient care. Each patient’s particular condition will have to be taken into careful consideration when designing biomimetic NPs for PTT and selecting which other treatment modalities to apply in combination with this therapy. The future of biomimetic NPs for PTT lies in solving these issues to achieve precise thermal ablation of solid-tumor cancers while providing specific, personalized, and maximally effective therapy for individual patients.