Cascade Immune Activation of Self-Delivery Biomedicine for Photodynamic Immunotherapy Against Metastatic Tumor

Photodynamic therapy (PDT) can generate reactive oxygen species (ROS) to cause cell apoptosis and induce immunogenic cell death (ICD) to activate immune response, becoming a promising antitumor modality. However, the overexpressions of indoleamine 2,3-dioxygenase (IDO) and programmed cell death ligand 1 (PD-L1) on tumor cells would reduce cytotoxic T cells infiltration and inhibit the immune activation. In this paper, a simple but effective nanosystem is developed to solve these issues for enhanced photodynamic immunotherapy. Specifically, it has been constructed a self-delivery biomedicine (CeNB) based on photosensitizer chlorine e6 (Ce6), IDO inhibitor (NLG919), and PD1/PDL1 blocker (BMS-1) without the need for extra excipients. Of note, CeNB possesses fairly high drug content (nearly 100%), favorable stability, and uniform morphology. More importantly, CeNB-mediated IDO inhibition and PD1/PDL1 blockade greatly improve the immunosuppressive tumor microenvironments to promote immune activation. The PDT of CeNB not only inhibits tumor proliferation but also induces ICD response to activate immunological cascade. Ultimately, self-delivery CeNB tremendously suppresses the tumor growth and metastasis while leads to a minimized side effect. Such simple and effective antitumor strategy overcomes the therapeutic resistance against PDT-initiated immunotherapy, suggesting a potential for metastatic tumor treatment in clinic.     

NIR-II Imaging-Guided Mitochondrial-Targeting Organic Nanoparticles for Multimodal Synergistic Tumor Therapy

Effectively interfering energy metabolism in tumor cells and simultaneously activating the in vivo immune system to perform immune attacks are meaningful for tumor treatment. However, precisely targeted therapy is still a huge challenge. Herein, a mitochondrial-targeting phototheranostic system, FE-T nanoparticles (FE-T NPs) are developed to damage mitochondria in tumor cells and change the tumor immunosuppressive microenvironment. FE-T NPs are engineered by encapsulating the near-infrared (NIR) absorbed photosensitizer IR-FE-TPP within amphiphilic copolymer DSPE-SS-PEG-COOH for high-performing with simultaneous mitochondrial-targeting, near-infrared II (NIR-II) fluorescence imaging, and synchronous photothermal therapy (PTT) /photodynamic therapy (PDT) /immune therapy (IMT). In tumor treatment, the disulfide in the copolymer can be cleaved by excess intracellular glutathione (GSH) to release IR-FE-TPP and accumulate in mitochondria. After 808 nm irradiation, the mitochondrial localization of FE-T NPs generated reactive oxygen species (ROS), and hyperthermia, leading to mitochondrial dysfunction, photoinductive apoptosis, and immunogenic cell death (ICD). Notably, in situ enhanced PDT/PTT in vivo via mitochondrial-targeting with FE-T NPs boosts highly efficient ICD toward excellent antitumor immune response. FE-T NPs provide an effective mitochondrial-targeting phototheranostic nanoplatform for imaging-guided tumor therapy.     

Massively Evoking Immunogenic Cell Death by Focused Mitochondrial Oxidative Stress using an AIE Luminogen with a Twisted Molecular Structure

Immunogenic cell death (ICD) provides momentous theoretical principle for modern cancer immunotherapy. However, the currently available ICD inducers are still very limited and photosensitizer‐based ones can hardly induce sufficient ICD to achieve satisfactory cancer immunotherapy by themselves. Herein, an organic photosensitizer (named TPE‐DPA‐TCyP) with a twisted molecular structure, strong aggregation‐induced emission activity, and specific ability is reported for effectively inducing focused mitochondrial oxidative stress of cancer cells, which can serve as a much superior ICD inducer to the popularly used ones, including chlorin e6 (Ce6), pheophorbide A, and oxaliplatin. Furthermore, more effective in vivo ICD immunogenicity of TPE‐DPA‐TCyP than Ce6 is also demonstrated using a prophylactic tumor vaccination model. The underlying mechanism of the effectiveness and robustness of TPE‐DPA‐TCyP in inducing antitumor immunity and immune‐memory effect in vivo is verified by immune cell analyses. This study thus reveals that inducing focused mitochondrial oxidative stress is a highly effective strategy to evoke abundant and large‐scale ICD.     

Novel PdPtCu Nanozymes for Reprogramming Tumor Microenvironment to Boost Immunotherapy Through Endoplasmic Reticulum Stress and Blocking IDO-Mediated Immune Escape

Breaking immunosuppressive tumor microenvironment (TME) has unique effects on inhibiting tumor growth and recurrence. Here, an endoplasmic reticulum (ER) targeted PdPtCu nanozyme (PNBCT^ER) is prepared to boost immunotherapy. First, PNBCT^ER has three kinds of enzyme activities, including catalase (CAT), glutathione oxidase (GSHOx), and peroxidase (POD)-like activities, which can reshape the TME. Second, PNBCT^ER kills tumor cells by photodynamic therapy (PDT) and photothermal therapy (PTT). Third, guided by T^ER, PNBCT^ER not only realizes the combination therapy of PDT, PTT and chemodynamic therapy (CDT), but also damages the ER of tumor cells and actives antitumor immune response, which breaks through the immune blockade of TME. Finally, the NLG919 blocks the tryptophan/kynurenine immune escape pathway and reverses the immunosuppressive TME. The strategy that reshaping the TME by enzyme catalysis and breaking immunosuppression provides a novel way for the application of combination therapy in tumor.     

Photosensitizer and Autophagy Promoter Coloaded ROS‐Responsive Dendrimer‐Assembled Carrier for Synergistic Enhancement of Tumor Growth Suppression

Reactive oxygen species (ROS) generated during photodynamic therapy (PDT) can trigger autophagy. However, little research is focused on whether there is a synergistic anticancer effect with PDT if extra autophagy promoter or inhibitor is added. Here, it is found that autophagy promotion significantly enhances the PDT activity to cancer cells. Based on this preliminary result, a ROS‐sensitive self‐assembled dendrimer nanoparticle is exploited as a carrier to codeliver an autophagy promoter (rapamycin, Rapa) and photosensitizer (phthalocyanine, Pc) to the tumor. After entrapped by cancer cells and irradiated by light, the ROS generated in PDT process of Pc can trigger nanoparticle destruction to release Rapa, thus initiating the autophagy process and remarkably enhancing the efficacy of PDT, leading to efficient tumor suppression.     

A Dual‐Bioresponsive Drug‐Delivery Depot for Combination of Epigenetic Modulation and Immune Checkpoint Blockade

Patients with advanced melanoma that is of low tumor‐associated antigen (TAA) expression often respond poorly to PD‐1/PD‐L1 blockade therapy. Epigenetic modulators, such as hypomethylation agents (HMAs), can enhance the antitumor immune response by inducing TAA expression. Here, a dual bioresponsive gel depot that can respond to the acidic pH and reactive oxygen species (ROS) within the tumor microenvironment (TME) for codelivery of anti‐PD1 antibody (aPD1) and Zebularine (Zeb), an HMA, is engineered. aPD1 is first loaded into pH‐sensitive calcium carbonate nanoparticles (CaCO₃ NPs), which are then encapsulated in the ROS‐responsive hydrogel together with Zeb (Zeb‐aPD1‐NPs‐Gel). It is demonstrated that this combination therapy increases the immunogenicity of cancer cells, and also plays roles in reversing immunosuppressive TME, which contributes to inhibiting the tumor growth and prolonging the survival time of B16F10‐melanoma‐bearing mice.     

多功能Pt-Ce6纳米平台作为过氧化氢纳米酶和NIR-Ⅱ光热剂用于增强PDT/PTT肿瘤治疗

实体肿瘤的缺氧严重影响着基于氧气的光动力疗法(PDT)的效果.另外,单一治疗模式通常难以达到满意的治疗效果.为此,我们设计合成了一种多功能纳米复合材料Pt-Ce6用于克服肿瘤乏氧,实现PDT/PTT协同治疗.在该体系中,我们使用多孔Pt纳米粒子作为过氧化氢纳米酶、近红外二区(NIR-Ⅱ)光热转换剂和光敏剂二氢卟吩e6(...     

Integration of IR‐808 Sensitized Upconversion Nanostructure and MoS2 Nanosheet for 808 nm NIR Light Triggered Phototherapy and Bioimaging

Near infrared (NIR) light triggered phototherapy including photothermal therapy (PTT) and photodynamic therapy (PDT) affords superior outcome in cancer treatment. However, the reactive oxygen species (ROS) generated by NIR‐excited upconversion nanostructure is limited by the feeble upconverted light which cannot activate PDT agents efficiently. Here, an IR‐808 dye sensitized upconversion nanoparticle (UCNP) with a chlorin e6 (Ce6)‐functionalized silica layer is developed for PDT agent. The two booster effectors (dye‐sensitization and core–shell enhancement) synergistically amplify the upconversion efficiency, therefore achieving superbright visible emission under low 808 nm light excitation. The markedly amplified red light subsequently triggers the photosensitizer (Ce6) to produce large amount of ROS for efficient PDT. After the silica is endowed with positive surface, these PDT nanoparticles can be easily grafted on MoS₂ nanosheet. As the optimal laser wavelength of UCNPs is consistent with that of MoS₂ nanosheet for PTT, the invented nanoplatform generates both abundant ROS and local hyperthermia upon a single 808 nm laser irradiation. Both the in vitro and in vivo assays validate that the innovated nanostructure presents excellent cancer cell inhibition effectiveness by taking advantages of the synergistic PTT and PDT, simultaneously, posing trimodal (upconversion luminescence/computed tomography (CT)/magnetic resonance imaging (MRI) imaging capability.     

Tailor-Made Autophagy Cascade Amplification Polymeric Nanoparticles for Enhanced Tumor Immunotherapy

Chemotherapeutics can induce immunogenic cell death (ICD) by triggering autophagy and mediate antitumor immunotherapy. However, using chemotherapeutics alone can only cause mild cell-protective autophagy and be incapable of inducing sufficient ICD efficacy. The participation of autophagy inducer is competent to enhance autophagy, so the level of ICD is promoted and the effect of antitumor immunotherapy is highly increased. Herein, tailor-made autophagy cascade amplification polymeric nanoparticles STF@AHPPE are constructed to enhance tumor immunotherapy. Arginine (Arg), polyethyleneglycol–polycaprolactone, and epirubicin (EPI) are grafted onto hyaluronic acid (HA) via disulfide bond to form the AHPPE nanoparticles and autophagy inducer STF-62247 (STF) is loaded. When STF@AHPPE nanoparticles target to tumor tissues and efficiently enter into tumor cells with the help of HA and Arg, the high glutathione concentration leads to the cleavage of disulfide bond and the release of EPI and STF. Finally, STF@AHPPE induces violent cytotoxic autophagy and strong ICD efficacy. As compared to AHPPE nanoparticles, STF@AHPPE nanoparticles kill the most tumor cells and show the more obvious ICD efficacy and immune activation ability. This work provides a novel strategy for combining tumor chemo-immunotherapy with autophagy induction.     

Rosmarinic Acid-Crosslinked Supramolecular Nanoassembly with Self-Regulated Photodynamic and Anti-Metastasis Properties for Synergistic Photoimmunotherapy

A primary concern about photodynamic therapy (PDT) is its inability to regulate the generation levels of reactive oxidative species (ROS) based on the complex microenvironment, resulting in the impairment toward normal tissues and immunosuppression. Besides, tumor metastasis also compromises PDT's efficacy and drives mortality. However, it is very challenging to achieve such two goals within one nanosystem. Here, the nanoassembly (CPR) with self-regulated photodynamic and antimetastasis properties comprises three parts: chlorin e6-conjugated β-cyclodextrin (CD-Ce6) acts as the main PDT agent and ferrocene (Fc)-terminated phenylboronic acid-containing conjugates entering into the cavity of CD-Ce6, as well as rosmarinic acid (RA)–boronic acid crosslinked shell. Compared with non-crosslinked counterpart, CPR displays better stability and enhanced tumor accumulation. Under laser irradiation, CPR generates plenty of ROS to damage tumor cells and induce immunogenic cell death. Mildly acidic TME partly cleaves the crosslinkers to dissociate antioxidant RAs from micelles, which together with Fc in CPR scavenge PDT-induced ROS in the TME. By contrast, under acidic lysosomal conditions, Fc catalyzes abundant H₂O₂ in tumor cells to produce highly cytotoxic •OH, while RA continuously reduces ferroptosis-generated Fc⁺ into Fc, both to augment the PDT efficacy in tumor cells. CPR also remarkably hinders the epithelial-mesenchymal transition to prevent the lung metastasis.     

Efficacy Dependence of Photodynamic Therapy Mediated by Upconversion Nanoparticles: Subcellular Positioning and Irradiation Productivity

Singlet oxygen (¹O₂), as an important kind of reactive oxygen species (ROS) and main therapeutic agent in photodynamic therapy (PDT), only have a half‐life of 40 ns and an effective radius of 20 nm, which cause significant obstacles for improving PDT efficacy. In this work, novel upconversion nanoparticle (UCN)‐based nanoplatforms are developed with a minimized distance between UCNs and a photosensitizer, protoporphyrin IX (PpIX), and a controllable payload of PpIX, to enhance and control ROS production. The ability of the nanoplatform to target different subcellular organelles such as cell membrane and mitochondria is demonstrated via surface modification of the nanoplatform with different targeting ligands. The results show that the mitochondria‐targeting nanoplatforms result in significantly increased capability of both tumor cell killing and inhibition of tumor growth. Subcellular targeting of nanoparticles leads to the death of cancer cells in different manners. However, the efficiency of ROS generation almost have no influence on the tumor cell viability during the period of evaluation. These findings suggest that specific subcellular targeting of the nanoplatforms enhances the PDT efficacy more effectively than the increase of ROS production, and may shed light on future novel designs of effective and controllable PDT nanoplatforms.     

Nanoengineered Immune Niches for Reprogramming the Immunosuppressive Tumor Microenvironment and Enhancing Cancer Immunotherapy

Cancer immunotherapies that harness the body's immune system to combat tumors have received extensive attention and become mainstream strategies for treating cancer. Despite promising results, some problems remain, such as the limited patient response rate and the emergence of severe immune‐related adverse effects. For most patients, the therapeutic efficacy of cancer immunotherapy is mainly limited by the immunosuppressive tumor microenvironment (TME). To overcome such obstacles in the TME, the immunomodulation of immunosuppressive factors and therapeutic immune cells (e.g., T cells and antigen‐presenting cells) should be carefully designed and evaluated. Nanoengineered synthetic immune niches have emerged as highly customizable platforms with a potent capability for reprogramming the immunosuppressive TME. Here, recent developments in nano‐biomaterials that are rationally designed to modulate the immunosuppressive TME in a spatiotemporal manner for enhanced cancer immunotherapy which are rationally designed to modulate the immunosuppressive TME in a spatiotemporal manner for enhanced cancer immunotherapy are highlighted.     

Tumor associated macrophages reprogrammed by targeted bifunctional bioorthogonal nanozymes for enhanced tumor immunotherapy

Cancer immunotherapy has emerged as a promising cancer treatment. However, its efficacy is often limited by the immunosuppressive tumor microenvironment (TME) in solid tumors. Herein, a new strategy has been presented by using bioorthogonal chemistry to reprogram TME. We designed a bifunctional mannose (Man) vector decorated palladium bioorthogonal nanozyme for in-situ synthesis of histone deacetylase inhibitor (HDACi) vorinostat (FDA approved) with the ability to remodel tumor microenvironment. To the best of our knowledge, this is the first report to use a bioorthogonal nanozyme for cancer immunotherapy. In particular, the nanozyme could preferentially accumulate in M2 macrophages (termed M2Φ) to achieve local M2 re-education, which effectively avoided unnecessary inflammation in normal tissues. Moreover, vorinostat-induced TME reprogramming was synergistic with peroxidase-like activity of the nanozyme, and achieved enhanced tumor synergistic immunotherapy. In colon cancer (CT26)-tumor-bearing BALB/c mice, the nanozyme demonstrated macrophages polarization targeting M2Φ and activation of innate immune system, resulting in significantly enhanced tumor growth inhibition. Our work not only provides a new effective way to reprogram TME in vivo, but also shed light on the design of novel bioorthogonal nanozymes for cancer immunotherapy.     

Binary Cooperative Prodrug Nanoparticles Improve Immunotherapy by Synergistically Modulating Immune Tumor Microenvironment

Checkpoint blockade immunotherapy is promising for clinical treatment of various malignant tumors. However, checkpoint blockade immunotherapy suffers from a low response rate due to insufficient tumor immunogenicity and the immunosuppressive tumor microenvironment (ITM). In this study, a tumor‐microenvironment‐activatable binary cooperative prodrug nanoparticle (BCPN) is rationally designed to improve immunotherapy by synergistically modulating the immune tumor microenvironment. BCPN is purely constructed from a tumor acidity and reduction dual‐responsive oxaliplatin (OXA) prodrug for triggering immunogenic cell death (ICD) and eliciting antitumor immunity, and a reduction‐activatable homodimer of NLG919 for inactivating indoleamine 2,3‐dioxygenase 1, which is a key regulator for ITM. Upon tumor‐acidity‐triggered cleavage of the poly(ethylene glycol) shell, PN shows negative to positive charge switch for enhanced tumor accumulation and deep penetration. OXA and NLG919 are then activated in the tumor cells via glutathione‐mediated reduction. It is demonstrate that activated OXA promotes intratumoral accumulation of cytotoxic T lymphocytes by triggering ICD of cancer cells. Meanwhile, NLG919 downregulates IDO‐1‐mediated immunosuppression and suppresses regulatory T cells. Most importantly, PN shows much higher efficiency than free OXA or the combination of free OXA and NLG919 to regress tumor growth and prevent metastasis of mouse models of both breast and colorectal cancer.     

构建酶敏感型嵌合肽用于肿瘤光动力学治疗

将疏水性光敏剂原卟啉(PpIX)和亲水性多肽结合,设计并合成一种刺激响应型两亲性嵌合肽PpIX-GGK(TPP)G-GFLGR8 GD(PTGR),利用该多肽在水溶液中能发生自组装行为,从而得到前药胶束。该胶束在RGD肽的作用下能有效富集在表面过度表达整合素αvβ3的肿瘤细胞周围;在R8穿膜肽的帮助下快速进入肿瘤细胞内;由于癌细胞细胞质内存在大量的组织蛋白酶B,其能够有效破坏GFLG多肽片段,导致前药胶束结构瓦解并释放出疏水性PpIX衍生物。此外,在三苯基膦(TPP)的引导下,组织蛋白酶B光敏剂原卟啉(PpIX)能高效富集在线粒体周围,并在特定光照条件下产生大量的活性氧(ROS),从而有效破坏线粒体,进而诱导细胞凋亡和坏死,实现光动力治疗(PDT)肿瘤的目的。这种将光敏剂运输到亚细胞部位的策略,为光动力治疗的高效发挥开辟了一条新的途径。     

Red‐Emitting Upconverting Nanoparticles for Photodynamic Therapy in Cancer Cells Under Near‐Infrared Excitation

Upconverting nanoparticles (UCNPs) have attracted considerable attention as potential photosensitizer carriers for photodynamic therapy (PDT) in deep tissues. In this work, a new and efficient NIR photosensitizing nanoplatform for PDT based on red‐emitting UCNPs is designed. The red emission band matches well with the efficient absorption bands of the widely used commercially available photosensitizers (Ps), benefiting the fluorescence resonance energy transfer (FRET) from UCNPs to the attached photosensitizers and thus efficiently activating them to generate cytotoxic singlet oxygen. Three commonly used photosensitizers, including chlorine e6 (Ce6), zinc phthalocyanine (ZnPc) and methylene blue (MB), are loaded onto the alpha‐cyclodextrin‐modified UCNPs to form Ps@UCNPs complexes that efficiently produce singlet oxygen to kill cancer cells under 980 nm near‐infrared excitation. Moreover, two different kinds of drugs are co‐loaded onto these nanoparticles: chemotherapy drug doxorubicin and PDT agent Ce6. The combinational therapy based on doxorubicin (DOX)‐induced chemotherapy and Ce6‐triggered PDT exhibits higher therapeutic efficacy relative to the individual means for cancer therapy in vitro.     

Photosensitive Nanoparticles Combining Vascular‐Independent Intratumor Distribution and On‐Demand Oxygen‐Depot Delivery for Enhanced Cancer Photodynamic Therapy

In drug delivery, the poor tumor perfusion results in disappointing therapeutic efficacy. Nanomedicines for photodynamic therapy (PDT) greatly need deep tumor penetration due to short lifespan and weak diffusion of the cytotoxic reactive oxygen species (ROS). The damage of only shallow cells can easily cause invasiveness and metastasis. Moreover, even if the nanomedicines enter into deeper lesion, the effectiveness of PDT is limited due to the hypoxic microenvironment. Here, a deep penetrating and oxygen self‐sufficient PDT nanoparticle is developed for balanced ROS distribution within tumor and efficient cancer therapy. The designed nanoparticles (CNPs/IP) are doubly emulsified (W/O/W) from poly(ethylene glycol)‐poly(ε‐caprolactone) copolymers doped with photosensitizer IR780 in the O layer and oxygen depot perfluorooctyl bromide (PFOB) inside the core, and functionalized with the tumor penetrating peptide Cys‐Arg‐Gly‐Asp‐Lys (CRGDK). The CRGDK modification significantly improves penetration depth of CNPs/IP and makes the CNPs/IP arrive at both the periphery and hypoxic interior of tumors where the PFOB releases oxygen, effectively alleviating hypoxia and guaranteeing efficient PDT performance. The improved intratumoral distribution of photosensitizer and adequate oxygen supply augment the sensitivity of tumor cells to PDT and significantly improve PDT efficiency. Such a nanosystem provides a potential platform for improved therapeutic index in anticancer therapy.     

Polysaccharide-Based Stimulus-Responsive Nanomedicines for Combination Cancer Immunotherapy

Cancer immunotherapy is a promising antitumor approach, whereas nontherapeutic side effects, tumor microenvironment (TME) intricacy, and low tumor immunogenicity limit its therapeutic efficacy. In recent years, combination immunotherapy with other therapies has been proven to considerably increase antitumor efficacy. However, achieving codelivery of the drugs to the tumor site remains a major challenge. Stimulus-responsive nanodelivery systems show controlled drug delivery and precise drug release. Polysaccharides, a family of potential biomaterials, are widely used in the development of stimulus-responsive nanomedicines due to their unique physicochemical properties, biocompatibility, and modifiability. Here, the antitumor activity of polysaccharides and several combined immunotherapy strategies (e.g., immunotherapy combined with chemotherapy, photodynamic therapy, or photothermal therapy) are summarized. More importantly, the recent progress of polysaccharide-based stimulus-responsive nanomedicines for combination cancer immunotherapy is discussed, with the focus on construction of nanomedicine, targeted delivery, drug release, and enhanced antitumor effects. Finally, the limitations and application prospects of this new field are discussed.     

Photosensitizer‐Conjugated Albumin−Polypyrrole Nanoparticles for Imaging‐Guided In Vivo Photodynamic/Photothermal Therapy

Conjugated polymers with strong absorbance in the near‐infrared (NIR) region have been widely explored as photothermal therapy agents due to their excellent photostability and high photothermal conversion efficiency. Herein, polypyrrole (PPy) nanoparticles are fabricated by using bovine serum albumin (BSA) as the stabilizing agent, which if preconjugated with photosensitizer chlorin e6 (Ce6) could offer additional functionalities in both imaging and therapy. The obtained PPy@BSA‐Ce6 nanoparticles exhibit little dark toxicity to cells, and are able to trigger both photodynamic therapy (PDT) and photothermal therapy (PTT). As a fluorescent molecule that in the meantime could form chelate complex with Gd³⁺, Ce6 in PPy@BSA‐Ce6 nanoparticles after being labeled with Gd³⁺ enables dual‐modal fluorescence and magnetic resonance (MR) imaging, which illustrate strong tumor uptake of those nanoparticles after intravenous injection into tumor‐bearing mice. In vivo combined PDT and PTT treatment is then carried out after systemic administration of PPy@BSA‐Ce6, achieving a remarkably improved synergistic therapeutic effect compared to PDT or PTT alone. Hence, a rather simple one‐step approach to fabricate multifunctional nanoparticles based on conjugated polymers, which appear to be promising in cancer imaging and combination therapy, is presented.     

Photosensitizer–Gold Nanorod Composite for Targeted Multimodal Therapy

In this work, a DNA inter‐strand replacement strategy for therapeutic activity is successfully designed for multimodal therapy. In this multimodal therapy, chlorin e6 (Ce6) photosensitizer molecules are used for photodynamic therapy (PDT), while aptamer‐AuNRs, are used for selective binding to target cancer cells and for photothermal therapy (PTT) with near infrared laser irradiation. Aptamer Sgc8, which specifically targets leukemia T cells, is conjugated to an AuNR by a thiol‐Au covalent bond and then hybridized with a Ce6‐labeled photosensitizer/reporter to form a DNA double helix. When target cancer cells are absent, Ce6 is quenched and shows no PDT effect. However, when target cancer cells are present, the aptamer changes structure to release Ce6 to produce singlet oxygen for PDT upon light irradiation. Importantly, by combining photosensitizer and photothermal agents, PTT/PDT dual therapy supplies a more effective therapeutic outcome than either therapeutic modality alone.