Tumor Microenvironment‐Responsive Mesoporous MnO2‐Coated Upconversion Nanoplatform for Self‐Enhanced Tumor Theranostics

The insufficient blood flow and oxygen supply in solid tumor cause hypoxia, which leads to low sensitivity of tumorous cells and thus causing poor treatment outcome. Here, mesoporous manganese dioxide (mMnO₂) with ultrasensitive biodegradability in a tumor microenvironment (TME) is grown on upconversion photodynamic nanoparticles for not only TME‐enhanced bioimaging and drug release, but also for relieving tumor hypoxia, thereby markedly improving photodynamic therapy (PDT). In this nanoplatform, mesoporous silica coated upconversion nanoparticles (UCNPs@mSiO₂) with covalently loaded chlorin e6 are obtained as near‐infrared light mediated PDT agents, and then a mMnO₂ shell is grown via a facile ultrasonic way. Because of its unique mesoporous structure, the obtained nanoplatform postmodified with polyethylene glycol can load the chemotherapeutic drug of doxorubicin (DOX). When used for antitumor application, the mMnO₂ degrades rapidly within the TME, releasing Mn²⁺ ions, which couple with trimodal (upconversion luminescence, computed tomography (CT), and magnetic resonance imaging) imaging of UCNPs to perform a self‐enhanced imaging. Significantly, the degradation of mMnO₂ shell brings an efficient DOX release, and relieve tumor hypoxia by simultaneously inducing decomposition of tumor endogenous H₂O₂ and reduction of glutathione, thus achieving a highly potent chemo‐photodynamic therapy.     

Ultralong Circulating Lollipop‐Like Nanoparticles Assembled with Gossypol,Doxorubicin, and Polydopamine via π–π Stacking for Synergistic Tumor Therapy

Long blood circulation in vivo remains a challenge to dual‐drug‐loaded nanocarriers for synergistic chemotherapy. Herein, a novel strategy to prepare lollipop‐like dual‐drug‐loaded nanoparticles (DOX–PDA–gossypol NPs) is developed based on the self‐assembly of gossypol, doxorubicin (DOX), and polydopamine (PDA) via π–π stacking. Dopamine polymerizes to PDA and fills the gaps between the gossypol and DOX molecules to form the super compact long‐circulating nanoparticles. The DOX–PDA–gossypol NPs show a suitable particle size of 59.6 ± 9.6 nm, high drug loading of 91%, superb stability, high maximum‐tolerated dose (MTD) of over 60 mg kg^‐1, and negligible toxicity. These NPs also exhibit pH‐dependent drug release and low combination index (0.23). Notably, they show dramatically ultralong blood circulation (>192 h) with elimination half times 458‐fold and 258‐fold longer than that of free DOX and free gossypol, respectively. These values are markedly higher than most of the reported results. Therefore, the DOX–PDA–gossypol NPs have a high tumor accumulation of 12% remaining on the 8th day postinjection. This characteristic contributes to the excellent tumor comprehensive synergistic therapeutic efficacy (TIR > 90%) with low administration dosage and is benefitted for widening the drug therapeutic window. Thus, the proposed strategy has remarkable potential for tumor synergistic therapy.     

Traceable Nanoparticles with Spatiotemporally Controlled Release Ability for Synergistic Glioblastoma Multiforme Treatment

Doxorubicin (DOX), one of the most widely used clinical antineoplastics, has ineffective therapeutic efficacy on glioblastoma multiforme (GBM) with extremely short survival time due to many obstacles such as blood–brain barrier (BBB), tumor angiogenesis, and glioblastoma stem cells (GSCs). To overcome, biocompatible nanoparticles named CARD‐B6 loading three clinical drugs are developed. Unlike other nanomedicines, CARD‐B6, with the ability of spatiotemporally controlled release, maximize the effectiveness of DOX. (1) After CARD‐B6 cross the BBB via B6, combretastatin A4 that is first released via protonation of poly (β‐amino ester) specifically destroys angiogenesis to facilitate the interaction between GBM and CARD‐B6. (2) Internalized into glioblastoma cells later, DOX is released via the breakage of amido bond to induce apoptosis, which is facilitated by the simultaneously released all‐trans retinoic acid (ATRA). (3) After endocytosis into GSCs, the rapidly released ATRA induces the GSCs differentiation and downregulates the survival pathways, which enhances the sensitivity of GSCs to the subsequently released DOX. This synergistic antitumor effect significantly extends survival time of GBM mouse model. CARD‐B6 are traced by superparamagnetic iron oxide nanocubes with high r₂ relaxivity for magnetic resonance imaging. Therefore, the traceable CARD‐B6 with spatiotemporally controlled release ability are emerging as a powerful platform for GBM treatment.     

Biomimetic Copper Sulfide for Chemo‐Radiotherapy: Enhanced Uptake and Reduced Efflux of Nanoparticles for Tumor Cells under Ionizing Radiation

Combined chemo‐radiotherapy is one of most widely applied treatments for clinical cancer therapy. Herein, it is found in this carefully designed study that ionizing radiation (e.g., X‐ray) can significantly increase the cell uptake of many different types of nanoparticles, and meanwhile obviously reduce their efflux. Such a phenomenon, which is not observed for small molecule drug such as doxorubicin (DOX), may be attributed to the X‐ray‐induced cell cycle change and upregulation of Caveolin‐1, a key protein in the caveolin‐dependent endocytosis pathway. Biomimetic copper sulfide nanoparticles, which are synthesized using melanin as the template and functionalized with polyethylene glycol (PEG), are then chosen as a platform for the combined chemo‐radiotherapy. Such CuS@Melanin‐PEG nanoparticles, while being able to load chemotherapeutics (e.g., DOX), can also act as a radiosensitizer to promote X‐ray induced cell apoptosis. In addition, although the overall tumor accumulation of CuS@Melanin‐PEG/DOX post intravenous injection is not significantly changed for tumors exposed to X‐ray, X‐ray radiation can result in obviously increased tumor cell uptake of drug‐loaded nanoparticles, subsequently leading to excellent synergistic antitumor therapeutic effect. A nanoplatform is developed with great performance in chemo‐radiotherapy, as well as uncovers a general synergistic mechanism particularly suitable for nanoparticle‐based chemo‐radiotherapy.     

Enzyme-Activated Prodrug-Based Smart Liposomes Specifically Enhance Tumor Hemoperfusion with Efficient Drug Delivery to Pancreatic Cancer Cells and Stellate Cells

Tumor-specific enhanced delivery of chemotherapeutics and modulators to tumor cells and activated pancreatic stellate cells (aPSCs), respectively, represents safer and more effective therapy for pancreatic cancer. Herein, a membrane type 1-matrix metalloproteinase (MT1-MMP)-cleavable spacer is used to assemble low-density cRGDfK onto thermosensitive liposomes loaded with phosphorylated calcipotriol (PCAL) and doxorubicin (DOX), yielding MR-T-PD. The liposome-linked cRGDfK prodrug on MR-T-PD surface is first activated by MT1-MMP, which is selectively expressed on tumor endothelial cells, to release cRGDfK. The free cRGDfK specifically promotes tumor angiogenesis, leading to 3.4-fold higher accumulation and a wider distribution of MR-T-PD in tumors. Furthermore, MR-T-PD rapidly releases PCAL and DOX into the interstitium under heat treatment. The released DOX enters tumor cells to induce apoptosis, whereas the PCAL prodrug is converted to CAL by alkaline phosphatase on the surface of aPSCs; CAL can then enter aPSCs to induce quiescence and promote the antitumor effect of DOX. Finally, by enhancing the exposure of DOX and CAL to tumor cells and aPSCs, respectively, in a tumor-specific manner, MR-T-PD exerts superior efficacy (a 5.9-fold decrease in tumor weight) without causing additional side effects. Overall, this prodrug-based smart liposome system represents a promising paradigm for pancreatic cancer therapy.     

Long Circulation Red‐Blood‐Cell‐Mimetic Nanoparticles with Peptide‐Enhanced Tumor Penetration for Simultaneously Inhibiting Growth and Lung Metastasis of Breast Cancer

Limited blood circulation and poor tumor penetration are two main obstacles hampering the clinical translation of conventional nanosized drug delivery systems (NDDS). Here, red‐blood‐cell (RBC)‐mimetic nanoparticles (NPs) with long circulation and peptide‐enhanced tumor penetration for treating metastatic breast cancer are reported. The RBC‐mimetic NPs are composed of a paclitaxel (PTX)‐loaded polymeric core and a hydrophilic RBC vesicle shell. The RBC‐mimetic NPs display dramatically elongated blood circulation with an elimination half time of 32.8 h, 5.8‐fold higher than that of the parental polymeric NPs (i.e., 5.6 h). Moreover, the experimental results demonstrate that the tumor penetration ability of the RBC‐mimetic NPs can be significantly improved by coadministrating with a tumor‐penetrating peptide iRGD. Antitumor studies using a metastatic 4T1 breast tumor model show that RBC‐mimetic NPs in combination with iRGD significantly inhibit over 90% of the tumor growth and suppress 95% of the lung metastasis, much more efficient than PTX‐loaded polymer NP alone or the combination of polymer NPs and iRGD. The results reveal the importance of both long circulation and tumor penetration of nanosized drugs for efficient cancer therapy, which can provide a new insight for NDDS design.     

Fabricating Aptamer‐Conjugated PEGylated‐MoS2/Cu1.8S Theranostic Nanoplatform for Multiplexed Imaging Diagnosis and Chemo‐Photothermal Therapy of Cancer

Fabricating theranostic nanoparticles combining multimode disease diagnosis and therapeutic has become an emerging approach for personal nanomedicine. However, the diagnostic capability, biocompatibility, and therapeutic efficiency of theranostic nanoplatforms limit their clinic widespread applications. Targeting to the theme of accurate diagnosis and effective therapy of cancer cells, a multifunctional nanoplatform of aptamer and polyethylene glycol (PEG) conjugated MoS₂ nanosheets decorated with Cu_1.8S nanoparticles (ATPMC) is developed. The ATPMC nanoplatform accomplishes photoluminescence imaging, photoacoustic imaging, and photothermal imaging for in vitro and in vivo tumor cells imaging diagnosis. Meanwhile, the ATPMC nanoplatform facilitates selective delivery of gene probe to detect intracellular microRNA aberrantly expressed in cancer cells and anticancer drug doxorubicin (DOX) for chemotherapy. Moreover, the synergistic interaction of MoS₂ and Cu_1.8S renders the ATPMC nanoplatform with superb photothermal conversion efficiency. The ATPMC nanoplatform loaded with DOX displays near‐infrared laser‐induced programmed chemotherapy and advanced photothermal therapy, and the targeted chemo‐photothermal therapy presents excellent antitumor efficiency.     

A Multifunctional Nanoplatform against Multidrug Resistant Cancer: Merging the Best of Targeted Chemo/Gene/Photothermal Therapy

Synergistic therapy that combines chemo‐, gene‐, or photothermal means shows great potential for enhancing the therapeutic effects on cancers. Tumor‐targeted nanoparticles based on a doxorubicin (DOX)‐gated mesoporous silica nanocore (MSN) encapsulated with permeability glycoprotein (P‐gp) small interfering RNA (siRNA) and a polydopamine (PDA) outer layer for DOX loading and folic acid decoration are designed. The multifunctional nanoplatform tactfully integrates chemo‐ (DOX), gene‐ (P‐gp siRNA), and photothermal (PDA layer) substances in one system. In vitro results reveal that DOX release behaviors are both pH‐ and thermal‐responsive and the release of co‐delivered P‐gp siRNA is also pH‐dependent due to the pH‐cleavable DOX gatekeeper on MSN. In addition, due to the near‐infrared light‐responsive PDA outer layer and folic acid conjugation, the nanoparticles exhibit outstanding photothermal activity and selective cell targeting ability. Subsequently, in vitro and in vivo antitumor experiments both demonstrate the enhanced antitumor efficacy of the multifunctional nanoparticles, indicating the significance of synergistic therapy combining chemo‐, gene‐, and photothermal treatments in one system.     

MAPK‐Targeted Drug Delivered by a pH‐Sensitive MSNP Nanocarrier Synergizes with PD‐1 Blockade in Melanoma without T‐Cell Suppression

The combination of BRAF/MEK‐targeted therapy with immune checkpoint blockade is regarded as a promising regimen for patients with metastatic melanoma due to their complementary advantages. However, MEK‐inhibitor‐induced T‐cell toxicity impedes effective cooperation. In this experiment, a pH‐responsive on‐demand controlled release mesoporous silica nanoparticles (MSNPs) system is designed. Fluorescein‐isothiocyanate‐loaded MSNP can be specifically delivered into tumor cells rather than T‐cells. MEK‐inhibitor‐loaded MSNP avoids proliferative and functional inhibitions of T‐cells, while preserving growth suppression of tumor cells in vitro. In an in vivo model, MSNP encapsulation reverses the MEK‐inhibitor‐induced suppression of activated CD8⁺ T‐cells, and enhances the secretion of INF‐γ and IL‐2. The combination of BRAF inhibitor plus MSNP‐loaded MEK inhibitor and anti‐PD‐1 antibody synergistically inhibits tumor growth via promoting robust immune‐related antitumor response. This work provides a novel and generalized framework for combining T‐cell‐impaired targeted therapy and immune checkpoint blockade by using a nanoparticle‐based delivery system.     

Phenylboronic Acid‐Decorated Chondroitin Sulfate A‐Based Theranostic Nanoparticles for Enhanced Tumor Targeting and Penetration

Phenylboronic acid‐functionalized chondroitin sulfate A (CSA)–deoxycholic‐acid (DOCA)‐based nanoparticles (NPs) are prepared for tumor targeting and penetration. (3‐Aminomethylphenyl)boronic acid (AMPB) is conjugated to CSA–DOCA conjugate via amide bond formation, and its successful synthesis is confirmed using proton nuclear magnetic resonance spectroscopy (¹H‐NMR). Doxorubicin (DOX)‐loaded CSA–DOCA–AMPB NPs with a mean diameter of ≈200 nm, a narrow size distribution, negative zeta potential, and spherical morphology are prepared. DOX release from NPs is enhanced at acidic pH compared to physiological pH. CSA–DOCA–AMPB NPs exhibit improved cellular uptake in A549 (human lung adenocarcinoma) cells and penetration into A549 multicellular spheroids compared to CSA–DOCA NPs as evidenced by confocal laser scanning microscopy and flow cytometry. In vivo tumor targeting and penetrating by CSA–DOCA–AMPB NPs, based on both CSA–CD44 receptor and boronic acid–sialic acid interactions, is revealed using near‐infrared fluorescence (NIRF) imaging. Penetration of NPs to the core of the tumor mass is observed in an A549 tumor xenografted mouse model and verified by three‐dimensional NIRF imaging. Multiple intravenous injections of DOX‐loaded CSA–DOCA–AMPB NPs efficiently inhibit the growth of A549 tumor in the xenografted mouse model and increase apoptosis. These boronic acid‐rich NPs are promising candidates for cancer therapy and imaging.     

Nutlin‐3a and Cytokine Co‐loaded Spermine‐Modified Acetalated Dextran Nanoparticles for Cancer Chemo‐Immunotherapy

The combination of chemo‐ and immunotherapy represents one promising strategy to overcome the existent challenges in the present‐day anticancer therapy. Here, spermine‐modified acetalated dextran nanoparticles (Sp‐AcDEX NPs), co‐loaded with the non‐genotoxic molecule Nutlin‐3a (Nut3a), and the cytokine granulocyte–macrophage colony‐stimulating factor (GM‐CSF), are developed to induce cancer cell death and create a specific antitumor immune response. These polymeric NPs release Nut3a in a pH dependent fashion and induce endosomal escape. Due to Nut3a, the loaded NPs exert specific toxicity toward wild‐type p53 cancer cells while avoiding toxicity in immune cells. Furthermore, the NPs show intrinsic immune adjuvancy on monocyte derived‐dendritic cells, upregulating the expression of cell surface CD83 and CD86 costimulatory markers. Finally, it is examined that by inducing MCF‐7 breast cancer cell death and acting as immune adjuvants, the NPs can downregulate the expression of IL‐10 and upregulate IL‐1β, leading to proliferation of CD3⁺ and cytotoxic CD8⁺ T cells. Overall, the study suggests that Sp‐AcDEX NPs loaded with Nut3a and GM‐CSF is a promising system for chemo‐immunotherapy, capable of inducing tumor cell death and stimulating immune response.     

A Versatile Nanotheranostic Agent for Efficient Dual‐Mode Imaging Guided Synergistic Chemo‐Thermal Tumor Therapy

The integration of efficient imaging for diagnosis and synergistic tumor therapy into a single‐component nanoplatform is much promising for high efficacy tumor treatment but still in a great challenge. Herein, a smart and versatile nanotheranostic platform based on hollow mesoporous Prussian blue nanoparticles (HMPBs) with perfluoropentane (PFP) and doxorubicin (DOX) inside, has been designed, for the first time, to achieve the distinct in vivo synergistic chemo‐thermal tumor therapy and synchronous diagnosis and monitoring by ultrasound (US)/photoacoustic (PA) dual mode imaging. The prepared HMPBs show excellent photothermal conversion properties with large molar extinction coefficient (≈1.2 × 10¹¹m ^?1 cm^?1) and extremely high photothermal conversion efficiency (41.4%). Such a novel theranostic nanoplatform is expected to overcome the inevitable tumor recurrence and metastasis resulting from the inhomogeneous ablation of single thermal therapy, which will find a promising prospect in the application of noninvasive cancer therapy.     

Versatile Prodrug Nanoparticles for Acid‐Triggered Precise Imaging and Organelle‐Specific Combination Cancer Therapy

Integration of chemotherapy with photodynamic therapy (PDT) has been emerging as a novel strategy for treatment of triple negative breast cancer (TNBC). However, the clinical translation of this approach is hindered by the unwanted dark toxicity due to the “always‐on” model and low tumor specificity of currently approved photosensitizer (PS). Here, the design of a multifunctional prodrug nanoparticle (NP) is described for precise imaging and organelle‐specific combination cancer therapy. The prodrug NP is composed of a newly synthesized oxaliplatin prodrug, hexadecyl‐oxaliplatin‐trimethyleneamine (HOT), an acid‐activatable PS, derivative of Chlorin e6 (AC), and functionalized with a targeting ligand iRGD for tumor homing and penetration. HOT displays much higher antitumor efficiency than oxaliplatin by simultaneously inducing mitochondria depolarizing and DNA cross‐linking. AC is specifically activated in the orthotopic or metastatic TNBC tumor for fluorescence imaging and PDT, while it remains inert in blood circulation to minimize the dark toxicity. Under the guide of acid‐activatable fluorescence imaging, PDT and chemotherapy can be synergistically performed for highly efficient regression of TNBC. Taken together, this versatile prodrug nanoplatform could achieve tumor‐specific imaging and organelle‐specific combination therapy, which can provide an alternative option for cancer theranostic.     

Integrated Combination Treatment Using a “Smart” Chemotherapy and MicroRNA Delivery System Improves Outcomes in an Orthotopic Colorectal Cancer Model

Mesoporous silica nanoparticles (MSN) can load and deliver potentially synergistic anticancer agents such as small molecule cytotoxics (like doxorubicin, DOX) and nucleic acids (like microRNA, miRNA). However, these cargos have different underlying chemical properties so overcoming respective intracellular delivery barriers is a key consideration. Strategies to deliver DOX from MSN frequently employ pH‐driven mechanisms that are restricted to the acidic environment of lysosomes. Conversely, strategies to deliver miRNA make use of approaches that deliberately compromise lysosomal membrane integrity to enable cytosolic delivery of the payload. To reconcile these two needs (lysosomal delivery of DOX and intracellular delivery of miRNA), a new methodology by “weaving” polyethylenimine on the MSN surface through disulfide bonds to achieve superior delivery of chemotherapy (DOX) and miRNA therapy (using miRNA‐145) is developed. Furthermore, an active targeting strategy based on a peptide ligand with affinity to glucose‐regulated protein 78 (GRP78), a cell surface protein overexpressed in colorectal carcinoma, is developed. The active targeting approach results in enhanced synergistic antitumor effect both in vitro and in vivo in an orthotopic murine model of colorectal cancer. Taken together, this work demonstrates the capability and advantages of “smart” MSN delivery systems to deliver anticancer cargo appropriately to targeted cancer cells.     

Cancer Cell Membrane‐Biomimetic Oxygen Nanocarrier for Breaking Hypoxia‐Induced Chemoresistance

The inadequate oxygen supply in solid tumor causes hypoxia, which leads to drug resistance and poor chemotherapy outcomes. To solve this problem, a cancer cell membrane camouflaged nanocarrier is developed with a polymeric core encapsulating hemoglobin (Hb) and doxorubicin (DOX) for efficient chemotherapy. The designed nanoparticles (DHCNPs) retain the cancer cell adhesion molecules on the surface of nanoparticles for homologous targeting and possess the oxygen‐carrying capacity of Hb for O₂‐interfered chemotherapy. The results show that DHCNPs not only achieve higher tumor specificity and lower toxicity by homologous targeting but also significantly reduce the exocytosis of DOX via suppressing the expressions of hypoxia‐inducible factor‐1α, multidrug resistance gene 1, and P‐glycoprotein, thus resulting in safe and high‐efficient chemotherapy. This work presents a new paradigm for targeted oxygen interference therapy by conquering hypoxia‐involved therapeutic resistance and achieves effective treatment of solid tumors.     

Long‐Circulating Drug‐Dye‐Based Micelles with Ultrahigh pH‐Sensitivity for Deep Tumor Penetration and Superior Chemo‐Photothermal Therapy

Nanocarriers for chemo‐photothermal therapy suffer from insufficient retention at the tumor site and poor penetration into tumor parenchyma. A smart drug‐dye‐based micelle is designed by making the best of the structural features of small‐molecule drugs. P‐DOX is synthesized by conjugating doxorubicin (DOX) with poly(4‐formylphenyl methacrylate‐co‐2‐(diethylamino) ethyl methacrylate)‐b‐polyoligoethyleneglycol methacrylate (P(FPMA‐co‐DEA)‐b‐POEGMA) via imine linkage. Through the π–π stacking interaction, IR780, a near‐infrared fluorescence dye as well as a photothermal agent, is integrated into the micelles (IR780‐PDMs) with the P‐DOX. The IR780‐PDMs show remarkably long blood circulation (t_1/2β = 22.6 h). As a result, a progressive tumor accumulation and retention are presented, which is significant to the sequential drug release. Moreover, when entering into a moderate acidic tumor microenvironment, IR780‐PDMs can dissociate into small‐size conjugates and IR780, which obviously increases the penetration depth of drugs, and then improves the lethality to deep‐seated tumor cells. Owing to the high delivery efficiency and superior chemo‐photothermal therapeutic efficacy of IR780‐PDMs, 97.6% tumor growth in the A549 tumor‐bearing mice is suppressed with a low dose of intravenous injection (DOX, 1.5 mg kg^?1; IR780, 0.8 mg kg^?1). This work presents a brand‐new strategy for long‐acting intensive cancer therapy.     

BPA-Containing Polydopamine Nanoparticles for Boron Neutron Capture Therapy in a U87 Glioma Orthotopic Model

Boron neutron capture therapy (BNCT) is a promising therapy for refractory cancer based on the cytotoxic reaction of ¹⁰B (n, α) ⁷Li. Although two BNCT agents are clinically available, they are quickly metabolized and show modest enrichment in tumor sites, partially limiting BNCT widespread application. Consequently, novel agents that perform active targeting and show good biocompatibility have to be developed. Herein, boronophenylalanine-containing polydopamine (B-PDA) nanoparticles are easily fabricated by encapsulating boronophenylalanine (BPA) in polydopamine via nitrogen-boronate coordination. In this study, B-PDA achieves increased tumor accumulation and prolonged retention effects in the tumor site and superior antitumor activity post neutron irradiation in the orthotopic xenograft glioma model. In brief, this study offers a novel strategy for BPA delivery and may broaden the perspective on nanomedicine design for BNCT.     

A Dual‐FRET‐Based Versatile Prodrug for Real‐Time Drug Release Monitoring and In Situ Therapeutic Efficacy Evaluation

A dual‐Förster resonance energy transfer (FRET)‐based versatile prodrug (V‐prodrug), in which the fluorescence of both 5(6)‐carboxylfluorescein (FAM) and doxorubicin (DOX) can be quenched by 4‐(dimethylaminoazo)benzene‐4‐carboxylic acid (Dabcyl) with high quenching efficiency, is developed in this paper. The V‐prodrug can selectively bind to the α_vβ₃ integrin overexpressed cancer cells through the Arg‐Gly‐Asp (RGD) targeting moiety. After that, the acid‐mediated DOX release of the V‐prodrug can be real‐time monitored by the increase of the red fluorescence from DOX. Thereafter, DOX‐induced cell apoptosis can also be in situ assessed by the fluorescence recovery of the FAM, due to the caspase‐3‐mediated Asp‐Glu‐Val‐Asp (DEVD) peptide sequence cleavage. This novel prodrug provides a cascaded imaging of real‐time drug release and subsequent cell apoptosis, which enables the in situ detection of the cancer response and the therapeutic efficacy evaluation of the prodrug.     

All‐in‐One Phototheranostics: Single Laser Triggers NIR‐II Fluorescence/Photoacoustic Imaging Guided Photothermal/Photodynamic/Chemo Combination Therapy

Development of single near‐infrared (NIR) laser triggered phototheranostics for multimodal imaging guided combination therapy is highly desirable but is still a big challenge. Herein, a novel small‐molecule dye DPP‐BT is designed and synthesized, which shows strong absorption in the first NIR window (NIR‐I) and fluorescence emission in the second NIR region (NIR‐II). Such a dye not only acts as a dual‐modal contrast agent for NIR‐II fluorescence and photoacoustic (PA) imaging, but also serves as a combined therapeutic agent for photothermal therapy (PTT) and photodynamic therapy (PDT). The single NIR laser triggered all‐in‐one phototheranostic nanoparticles are constructed by encapsulating the dye DPP‐BT, chemotherapy drug DOX, and natural phase‐change materials with a folic acid functionalized amphiphile. Notably, under NIR laser irradiation, DOX can effectively release from such nanoparticles via NIR‐induced hyperthermia of DPP‐BT. By intravenous injection of such nanoparticles into Hela tumor‐bearing mice, the tumor size and location can be accurately observed via NIR‐II fluorescence/PA dual‐modal imaging. From in vitro and in vivo therapy results, such nanoparticles simultaneously present remarkable antitumor efficacy by PTT/PDT/chemo combination therapy, which is triggered by a single NIR laser. Overall, this work provides an innovative strategy to design and construct all‐in‐one nanoplatforms for clinical phototheranostics.