NIR-II Responsive Inorganic 2D Nanomaterials for Cancer Photothermal Therapy: Recent Advances and Future Challenges

Non-invasive cancer photothermal therapy (PTT) is a promising replacement for traditional cancer treatments. The second near-infrared region induced PTT (NIR-II PTT, 1000–1500 nm) with less energy dissipation has been developed for deeper-seated tumor treatment in recent years compared with the traditional first near-infrared light (750–1000 nm). In addition, the use of emerging inorganic 2D nanomaterials as photothermal agents (PTAs) further enhanced PTT efficiency due to their intrinsic photothermal properties. NIR-II light stimulated inorganic 2D nanomaterials for PTT is becoming a hot topic in both academic and clinical fields. This review summarizes the categories, structures, and photothermal conversion properties of inorganic 2D nanomaterials for the first time. The recent synergistic strategies of NIR-II responsive PTT combined with other treatment approaches including chemotherapy, chemodynamic therapy, photodynamic therapy, radiotherapy are summarized. The future challenges and perspectives on these 2D nanomaterials for NIR-II responsive PTT systems construction are further discussed.     

pH‐Responsive Cyanine‐Grafted Graphene Oxide for Fluorescence Resonance Energy Transfer‐Enhanced Photothermal Therapy

Stimuli‐responsive anticancer agents are of particular interest in the field of cancer therapy. Nevertheless, so far stimuli‐responsive photothermal agents have been explored with limited success for cancer photothermal therapy (PTT). In this work, as a proof‐of‐concept, a pH‐responsive photothermal nanoconjugate for enhanced PTT efficacy, in which graphene oxide (GO) with broad NIR absorbance and effective photothermal conversion efficiency is selected as a typical model receptor of fluorescence resonance energy transfer (FRET), and grafted cyanine dye (e.g., Cypate) acts as the donor of near‐infrared fluorescence (NIRF), is reported for the first time. The conjugate of Cypate‐grafted GO exhibits different conformations in aqueous solutions at various pH, which can trigger pH‐dependent FRET effect between GO and Cypate and thus induce pH‐responsive photothermal effect of GO‐Cypate. GO‐Cypate exhibits severe cell damage owing to the enhanced photothermal effect in lysosomes, and thus generate synergistic PTT efficacy with tumor ablation upon photoirradiation after a single‐dose intravenous injection. The photothermal nanoconjugate with broad NIR absorbance as the effective receptor of FRET can smartly convert emitted NIRF energy from donor cyanine dye into additional photothermal effect for improving PTT. These results suggest that the smart nanoconjugate can act as a promising stimuli‐responsive photothermal nanoplatform for cancer therapy.     

Anionic Solid Solution MXene for Low-Dosage NIR-II Tumor Photothermal Therapy

Due to the deep biological penetrability and therapeutic depth, the photothermal therapy over second near-infrared region (NIR-II) is booming against deep-seated tumors. Intensive endeavors are committed to looking for suitable photothermal agents (PTAs), but the progress seems not so satisfied toward the choice of PTA dosage. Herein, a comprehensive parameter, incident photon-to-thermal conversion coefficient (IPTCE), is used to evaluate the overall conversion of PTAs at different dosage, which will benefit for determining the optimized dosage of PTAs in pursuit of complete healing together with reduced long-term damages of nanodrugs. To prove the possibility, a series of anionic solid solution MXenes are chosen as hosts due to their versatile chemical compositions and correspondingly tunable light response. By deconvoluting fundamental structure–composition–property relationships, anionic regulation with extra electron injection leads to tunable free carrier densities and enhanced NIR-II harvesting. Ti₃C_1.23N_0.77 with high-level nitrogen exhibits extraordinary extinction coefficient (43.5 L g⁻¹ cm⁻¹) than other MXenes. The parameter of IPTCE can guide the choice of PTA concentration for complete photothermal healing in vitro and vivo. This proof-of-principle demonstration highlights synthetically tailoring of the light harvesting over NIR-II biowindow for a given host material by anionic regulation and further optimizes tumor photothermal therapy at low dose.     

Significant Enhancement of Photothermal and Photoacoustic Efficiencies for Semiconducting Polymer Nanoparticles through Simply Molecular Engineering

Semiconducting polymer nanoparticles (SP NPs) are employed as efficient nanoagents for “all‐in‐one” theranostic nanoplatforms with dual photoacoustic imaging (PAI) and photothermal therapy (PTT) functions based on their photothermal conversion effect. However, the mechanisms of tuning the PTT efficiency are still elusive, though several SP NPs with high photothermal efficiency are reported. Herein, two donor–acceptor (D–A) SP NPs PTIGSVS and PIIGSVS with the same donor unit but different acceptor units are designed and synthesized. Through tuning the acceptor unit, PTIGSVS shows more planar backbone structure, stronger D–A strength, redshifted absorption, enhanced extinction efficient, weakened emission properties, and more efficient nonradiative decay in comparison to the polymeric analogue PIIGSVS . Thus, PTIGSVS NPs present much higher photothermal conversion efficiencies (74%) than PIIGSVS NPs (11%), resulting in significantly enhanced in vitro and in vivo PAI and PTT performance. This contribution demonstrates that PTIGSVS NPs are superior PA/PTT agents for effective cancer theranostic and shed light on understanding the relationship between molecular structures and photothermal effect of CPs.     

Increasing Photothermal Efficacy by Simultaneous Intra‐ and Intermolecular Fluorescence Quenching

Recently, using in situ self‐assembly‐induced fluorescence quenching (i.e., intermolecular quenching denoted herein) of a photothermal agent (PTA) to enhance its photothermal efficiency has proven to be a successful photothermal therapy (PTT) strategy. But to the best of current knowledge, using simultaneous intra‐ and intermolecular fluorescence quenching of a PTA to additionally increase its photothermal efficacy has not been reported. Herein, employing a click condensation reaction and a rationally designed PTA Biotin‐Cystamine‐Cys‐Lys(Cypate)‐CBT ( 1 ), a “smart” strategy is developed of intracellular simultaneous intra‐ and intermolecular fluorescence quenching and applied it to largely increase the photothermal efficacy of the agent both in vitro and in vivo. After being internalized by biotin receptor‐overexpressing cancer cells, 1 is reduced by intracellular glutathione to initiate a CBT‐Cys condensation reaction (intramolecular quenching) and self‐assembly (intermolecular quenching) to form the nanoparticles 1‐NPs (simultaneous intra‐ and intermolecular fluorescence quenching). Experimental results indicate that 1‐NPs have higher fluorescence quenching efficiency than the control PTAs [Thiazole‐Lys(Cypate)‐Benzothiazole]₂ ( 1‐Dimer , intramolecular quenching), and nanoparticles of Cystamine‐Cys(Fmoc)‐Lys(Cypate)‐CBT ( 1‐Fmoc‐NPs , intermolecular quenching). It is envisioned that, by replacing the biotin group on 1 with other targeting warheads, the “smart” strategy is ready to increase the photothermal therapeutic efficiency of their corresponding diseases.     

Ultrafast Synthesis of Ultrasmall Poly(Vinylpyrrolidone)‐Protected Bismuth Nanodots as a Multifunctional Theranostic Agent for In Vivo Dual‐Modal CT/Photothermal‐Imaging‐Guided Photothermal Therapy

To elaborately fabricate real‐time monitoring and therapeutic function into a biocompatible nanoplatform is a promising route in the cancer therapy field. However, the package of diagnosis and treatment into a single‐“element” nanoparticle remains challenge. Herein, ultrasmall poly(vinylpyrrolidone)‐protected bismuth nanodots (PVP‐Bi nanodots) are successfully synthesized through an ultrafacile strategy (1 min only under ambient conditions). The nanodots are easy to synthesize in both laboratory and large scale using low‐cost bismuth ingredients. PVP‐Bi nanodots with ultrasmall size show good biocompatibility. Due to the high X‐ray attenuation ability of Bi element, PVP‐Bi nanodots have prominent performance on X‐ray computed tomography (CT) imaging. Moreover, PVP‐Bi nanodots exhibit a high photothermal conversion efficiency (η = 30%) because of the strong near‐infrared absorbance, which can serve as nanotheranostic agent for photothermal imaging and cancer therapy. The subsequent PVP‐Bi‐nanodot‐mediated photothermal therapy (PTT) result shows highly efficient ablation of cancer cells both in vitro and in vivo. PVP‐Bi nanodots can be almost completely excreted from mice after 7 d. Blood biochemistry and histology analysis suggests that PVP‐Bi nanodots have negligible toxicity. All the positive results reveal that PVP‐Bi nanodots produced through the ultrafacile method are promising single‐“element” nanotheranostic platform for dual‐modal CT/photothermal‐imaging‐guided PTT.     

PEGylated Micelle Nanoparticles Encapsulating a Non‐Fluorescent Near‐Infrared Organic Dye as a Safe and Highly‐Effective Photothermal Agent for In Vivo Cancer Therapy

Photothermal therapy (PTT), as a minimally invasive and highly effective cancer treatment approach, has received widespread attention in recent years. Tremendous effort has been devoted to explore various types of photothermal agents with high near‐infrared (NIR) absorbance for PTT cancer treatment. Despite many exciting progresses in the area, effective yet safe photothermal agents with good biocompatibility and biodegradability are still highly desired. In this work, a new organic PTT agent based on polyethylene glycol (PEG) coated micelle nanoparticles encapsulating a heptamethine indocyanine dye IR825 is developed, showing a strong NIR absorption band and a rather low quantum yield, for in vivo photothermal treatment of cancer. It is found that the IR825–PEG nanoparticles show ultra‐high in vivo tumor uptake after intravenous injection, and appear to be an excellent PTT agent for tumor ablation under a low‐power laser irradiation, without rendering any appreciable toxicity to the treated animals. Compared with inorganic nanomaterials and conjugated polymers being explored in PTT, the NIR‐absorbing micelle nanoparticles presented here may have the least safety concern while showing excellent treatment efficacy, and thus may be a new photothermal agent potentially useful in clinical applications.     

A NIR-II AIEgen-Based Supramolecular Nanodot for Peroxynitrite-Potentiated Mild-Temperature Photothermal Therapy of Hepatocellular Carcinoma

Compared to conventional photothermal therapy (PTT) which requires hyperthermia higher than 50 °C, mild-temperature PTT is a more promising antitumor strategy with much lower phototoxicity to neighboring normal tissues. However, the therapeutic efficacy of mild-temperature PTT is always restricted by the thermoresistance of cancer cells. To address this issue, a supramolecular drug nanocarrier is fabricated to co-deliver nitric oxide (NO) and photothermal agent DCTBT with NIR-II aggregation-induced emission (AIE) characteristic for mild-temperature PTT. NO can be effectively released from the nanocarriers in intracellular reductive environment and DCTBT is capable of simultaneously producing reactive oxygen species (ROS) and hyperthermia upon 808 nm laser irradiation. The generated ROS can further react with NO to produce peroxynitrite (ONOOˉ) bearing strong oxidization and nitration capability. ONOOˉ can inhibit the expression of heat shock proteins (HSP) to reduce the thermoresistance of cancer cells, which is necessary to achieve excellent therapeutic efficacy of DCTBT-based PTT at mild temperature (<50 °C). The antitumor performance of ONOOˉ-potentiated mild-temperature PTT is validated on subcutaneous and orthotopic hepatocellular carcinoma (HCC) models. This research puts forward an innovative strategy to overcome thermoresistance for mild-temperature PTT, which provides new inspirations to explore ONOOˉ-sensitized tumor therapy strategies.     

Intracellular Bottom-up Synthesis of Ultrasmall CuS Nanodots in Cancer Cells for Simultaneous Photothermal Therapy and COX-2 Inactivation

The clinical application of photothermal therapy (PTT) is limited by the accuracy of thermal damage and the risk of tumor metastasis and relapse induced by hyperthermia-related inflammation. Intracellular bottom-up synthesis (iBuS) of CuS nanoparticles from small-molecule precursors inside tumor cells triggered by tumor specific stimuli is a promising strategy to enhance the precision of PTT treatment and reduce the risk of nondegradable metal nanoparticles. Herein, monolocking nanoparticles (MLNPs) with Cu-meloxicam complexes encapsulated by human serum albumin (HSA) are reported, which efficiently form CuS nanodots via the elevated concentration of endogenous H₂S inside tumor cells and meanwhile release meloxicam for anti-inflammatory effects. The intracellular bottom-up fabrication of CuS nanodots is directly visualized by TEM. An enhanced PTT effect is observed with 4T1 cells caused by additional meloxicam-induced inactivation of the COX-2 enzyme. After systemic administration, MLNPs completely ablate tumors under laser exposure, simultaneously inhibiting the inflammation induced by photothermal damage, and can be cleared via the kidney into urine. This strategy provides a new route for activated multimodal therapy, which could be applicable to precisely combat cancer.     

Organic Semiconducting Macromolecular Dyes for NIR-II Photoacoustic Imaging and Photothermal Therapy

Owing to the unique advantages of photoacoustic imaging (PAI) and photothermal therapy (PTT) conducted over the near-infrared-II (NIR-II) window, the development of high-efficiency optical agents with NIR-II light responsiveness is of great significance. Despite the diversity of optical agents developed for NIR-II PAI and PTT, most of them are based on inorganic nanomaterials and small molecular dyes, whose biosafety and photostability need to be further assessed, respectively. Organic semiconducting macromolecular dyes (OSMDs) featuring a large semiconducting backbone are becoming alternative candidates for NIR-II PAI and PTT owing to their reliable biocompatibility, durable photostability, and ideal photothermal conversion capability. This paper reviews the current progress of OSMD-based PAI and PTT in the NIR-II optical window. The three main types of OSMDs with different skeleton architectures are introduced, and their applications for NIR-II PAI (tumor imaging, stem cell tracking, and vasculature imaging) and PTT (tumor ablation) are described. Viable strategies for further improving the NIR-II PAI performance of OSMDs are discussed. Finally, some major issues faced by OSMDs in NIR-II PAI and PTT are raised, and the future development directions of OSMDs are analyzed.     

Renal-Clearable Nickel-Doped Carbon Dots with Boosted Photothermal Conversion Efficiency for Multimodal Imaging-Guided Cancer Therapy in the Second Near-Infrared Biowindow

Photothermal agents with absorption in the second near-infrared (NIR-II) biowindow have attracted increasing attention for photothermal therapy (PTT) on account of their deeper tissue penetration capacity. However, most of the current NIR-II photothermal agents exhibit low photothermal conversion efficiency (PCE) and long-term biotoxicity. To overcome these shortcomings, herein, nickel and nitrogen co-doped carbon dots (Ni-CDs, ≈4.6 nm) are prepared via a facile one-pot hydrothermal approach for imaging-guided PTT in the NIR-II window. The Ni-CDs exhibit significant absorption in the NIR-II region with a distinguished PCE as high as 76.1% (1064 nm) and have excellent photostability and biocompatibility. Furthermore, the Ni-CDs can be employed as photothermal, photoacoustic, and magnetic resonance imaging contrast agents because of their outstanding photothermal effect and instinctive paramagnetic feature. The Ni-CDs demonstrate significant PTT efficacy of tumor upon 1064 nm irradiation with a low power density (0.5 W cm⁻²). The Ni-CDs can be eliminated from the body via a renal filtration pathway, thereby minimizing their long-term biotoxicity. Therefore, this work provides a simple and feasible approach to develop photothermal agents with remarkable PCE in the NIR-II region, presenting good biosafety for multimodal imaging-guided PTT of tumor.     

Hollow Nanostars with Photothermal Gold Caps and Their Controlled Surface Functionalization for Complementary Therapies

Gold nanoparticles exhibiting absorption in the desirable near‐infrared region are attractive candidates for photothermal therapy (PTT). Furthermore, the construction of one nanoplatform employing gold nanoparticles for complementary therapy is still a great challenge. Here, well‐defined unique hollow silica nanostars with encapsulated gold caps (starlike Au@SiO₂) are readily synthesized using a sacrificial template method. Ethanolamine‐functionalized poly(glycidyl methacrylate) (denoted as BUCT‐PGEA) brushes are then grafted controllably from the surface of starlike Au@SiO₂ nanoparticles via surface‐initiated atom transfer radical polymerization to produce starlike Au@SiO₂‐PGEA. The photothermal effect of gold caps with a cross cavity can be utilized for PTT. The interior hollow feature of starlike Au@SiO₂ nanoparticles endows them with excellent drug loading capability for chemotherapy, while the polycationic BUCT‐PGEA brushes on the surface provide good transfection performances for gene therapy, which will overcome the penetration depth limitation of PTT for tumor therapy. Compared with ordinary spherical Au@SiO₂‐PGEA counterparts, the starlike Au@SiO₂‐PGEA hybrids with sharp horns favor endocytosis, which can contribute to enhanced antitumor effectiveness. The rational integration of photothermal gold caps, hollow nanostars, and polycations through the facile strategy might offer a promising avenue for complementary cancer therapy.     

Thermoresponsive Nanogel‐Encapsulated PEDOT and HSP70 Inhibitor for Improving the Depth of the Photothermal Therapeutic Effect

Photothermal therapy (PTT), a new, noninvasive treatment measure, has recently drawn much attention. However, due to the limited penetration depth of near‐infrared (NIR) light, PTT is focused on treating superficial tumors. Improving the depth of the therapeutic effect is a bottleneck for successful PTT. To solve this problem, a new kind of nanoplatform (Nanogel+phenylethynesulfonamide (PES)) is fabricated by using a thermo‐responsive polymer shell (poly(N‐isopropylacrylamide‐co‐acrylic acid) to encapsulate 2‐PES, an effective heat shock protein 70 (HSP70) inhibitor, and poly(3,4‐ethylenedioxythiophene), a widely used photothermal coupling agent. Upon NIR irradiation, PES can be released from the Nanogel+PES when a thermo‐responsive phase transition occurs, which could restrain the function of HSP70 and reduces the cells' endurance to heat. In this way, a better therapeutic effect on deeper tissues is achieved with a relatively small rise in temperature. Therefore, with the advantages of the thermo‐responsive photothermal effect, coupled with the inhibition of HSP70, and minimal cytotoxicity, the Nanogel+PES appears to be a promising photothermal agent that can improve the depth of the PTT effect.     

Nanoagent-Promoted Mild-Temperature Photothermal Therapy for Cancer Treatment

Photothermal therapy (PTT), which utilizes near-infrared light-absorbing agents to ablate tumor, has emerged as a highly promising anticancer strategy and received intensive clinical trials in recent years. Mild-temperature PTT, which circumvents the limitations of conventional PTT (e.g., thermoresistance and adverse effects), is emerging and shows great potential in the forthcoming clinical applications. However, mild-temperature PTT without adjuvant therapy is not able to completely eradicate tumors because its therapeutic efficacy is dramatically impaired by its inferior heat intensity. As a result, strategies capable of enhancing the anticancer efficacy of mild-temperature PTT are urgently necessitated, which mainly rely on on-demand fabrication of functionalized nanoagents. In this review, the strategies of nanoagent-promoted mild-temperature PTT are highlighted. Furthermore, challenges and opportunities in this field are rationally proposed, and hopefully people can be encouraged by this promising anticancer therapy.     

Enhanced Antitumor Efficacy by 808 nm Laser‐Induced Synergistic Photothermal and Photodynamic Therapy Based on a Indocyanine‐Green‐Attached W18O49 Nanostructure

A novel nanoplatform based on tungsten oxide (W₁₈O₄₉, WO) and indocyanine green (ICG) for dual‐modal photothermal therapy (PTT) and photodynamic therapy (PDT) has been successfully constructed. In this design, the hierarchical unique nanorod‐bundled W₁₈O₄₉ nanostructures play roles in being not only as an efficient photothermal agent for PTT but also as a potential nanovehicle for ICG molecules via electrostatic adsorption after modified with trimethylammonium groups on their surface. It is found that the ability of ICG to produce cytotoxic reactive oxygen species for PDT is well maintained after being attached on the WO, thus the as‐obtained WO@ICG can achieve a synergistic effect of combined PTT and PDT under single 808 nm near‐infrared (NIR) laser excitation. Notably, compared with PTT or PDT alone, the enhanced HeLa cells lethality of the 808 nm laser triggered dual‐modal therapy is observed. The in vivo animal experiments have shown that WO@ICG has effective solid tumor ablation effect with 808 nm NIR light irradiation, revealing the potential of these nanocomposites as a NIR‐mediated dual‐modal therapeutic platform for cancer treatment.     

Photothermal Lysis of Engineered Bacteria to Modulate Amino Acid Metabolism against Tumors

Bacterial-mediated synergistic cancer therapy (BMSCT) is used as a promising tumor therapy approach. However, there are some disadvantages of bacterial therapy alone to be resolved, such as low tumor suppression rate in the treatment. In this study, a novel light-controlled engineered bacterial material which synergistically regulates amino acid metabolism to fight tumors is developed. It transcribes l -methionine-γ-lyase (MdeA) into Escherichia coli (E. coli) and loads the approved photothermal agent indocyanine green (ICG), namely E. coli-MdeA@ICG. Using the hypoxic tropism of E. coli, genetically engineered bacteria are first loaded with photothermal agents, then selectively accumulate and replicate in the tumor region. Under laser irradiation, photothermal lysis of E. coli-MdeA is performed to release the MdeA and consume the essential amino acid methionine (Met) in the tumor environment. In vitro cell experiments confirm that the E. coli-MdeA + NIR group can reach 90% of the 4T1 cells killing. In 4T1 tumor-bearing mouse models, E. coli-MdeA@ICG shows enhanced antitumor efficacy, along with 91.8% of the tumor growth inhibited. Apoptosis of tumor cells is induced under the dual action of photothermal therapy (PTT) and amino acid metabolism therapy. This strategy provides new ideas for the combination of synthetic biology and nanotechnology in anti-tumor.     

Tumor‐Penetrating Nanotherapeutics Loading a Near‐Infrared Probe Inhibit Growth and Metastasis of Breast Cancer

The tumor growth and metastasis is the leading reason for the high mortality of breast cancer. Herein, it is first reported a deep tumor‐penetrating photothermal nanotherapeutics loading a near‐infrared (NIR) probe for potential photothermal therapy (PTT) of tumor growth and metastasis of breast cancer. The NIR probe of 1,1‐dioctadecyl‐3,3,3,3‐tetramethylindotricarbocyanine iodide (DiR), a lipophilicfluorescent carbocyanine dye with strong light‐absorbing capability, is entrapped into the photothermal nanotherapeutics for PTT application. The DiR‐loaded photothermal nanotherapeutics (DPN) is homogeneous nanometer‐sized particles with the mean diameter of 24.5 ± 4.1 nm. Upon 808 nm laser irradiation, DPN presents superior production of thermal energy than free DiR both in vitro and in vivo. The cell proliferation and migration activities of metastatic 4T1 breast cancer cells are obviously inhibited by DPN in combination with NIR irradiation. Moreover, DPN can induce a higher accumulation in tumor and penetrate into the deep interior of tumor tissues. The in vivo PTT measurements indicate that the growth and metastasis of breast cancer are entirely inhibited by a single treatment of DPN with NIR irradiation. Therefore, the deep tumor‐penetrating DPN can provide a promising strategy for PTT of tumor progression and metastasis of breast cancer.     

pH Switchable Nanoplatform for In Vivo Persistent Luminescence Imaging and Precise Photothermal Therapy of Bacterial Infection

Photothermal therapy (PTT) is one of the most promising approaches to combat multidrug‐resistant bacteria with less potential to induce resistance and systemic toxicity. However, uncontrollable distribution of photothermal agents leads to lethal temperatures for normal cells, and failure to offer timely and effective antibacterial stewardship. A pH switchable nanoplatform for persistent luminescence imaging‐guided precise PTT to selectively destroy only pathological cells while protecting nearby normal cells in bacterial infected microenvironment is shown. The PLNP@PANI‐GCS is fabricated by grafting polyaniline (PANI) and glycol chitosan (GCS) onto the surface of persistent luminescence nanoparticles (PLNPs). It takes advantage of the long persistent luminescence of PLNPs to realize autofluorescence‐free imaging, the pH‐dependent light–heat conversion property of PANI to get a stronger photothermal effect at pH 6.5 than pH 7.4, and the pH environment responsive surface charge transition of GCS. Consequently, PLNP@PANI‐GCS enables effective response to bacterial‐infected acid region and electrostatic bonding to bacteria in vivo, ensuring the spatial accuracy of near‐infrared light irradiation and specific heating directly to bacteria. In vivo imaging‐guided PTT to bacterial infection abscess shows effective treatment. PLNP@PANI‐GCS has great potential in treating multidrug‐resistant bacterial infection with low possibility of developing microbial drug resistance and little harm to normal cells.     

Designing Bioinspired 2D MoSe2 Nanosheet for Efficient Photothermal‐Triggered Cancer Immunotherapy with Reprogramming Tumor‐Associated Macrophages

Nonspecific absorption and clearance of nanomaterials during circulation is the major cause for treatment failure in nanomedicine‐based cancer therapy. Therefore, herein bioinspired red blood cell (RBC) membrane is employed to camouflage 2D MoSe₂ nanosheets with high photothermal conversion efficiency to achieve enhanced hemocompatibility and circulation time by preventing macrophage phagocytosis. RBC–MoSe₂‐potentiated photothermal therapy (PTT) demonstrates potent in vivo antitumor efficacy, which triggers the release of tumor‐associated antigens to activate cytotoxic T lymphocytes and inactivate the PD‐1/PD‐L1 pathway to avoid immunologic escape. Furthermore, in the ablated tumor microenvironment, the tumor‐associated macrophages are effectively reprogrammed to tumoricidal M1 phenotype to potentiate the antitumor action. Taken together, this biomimetic functionalization thus provides a substantial advance in personalized PTT‐triggered immunotherapy for clinical translation.