Molecular Targeting‐Mediated Mild‐Temperature Photothermal Therapy with a Smart Albumin‐Based Nanodrug

Photothermal therapy (PTT) usually requires hyperthermia >50 °C for effective tumor ablation, which inevitably induces heating damage to the surrounding normal tissues/organs. Moreover, low tumor retention and high liver accumulation are the two main obstacles that significantly limit the efficacy and safety of many nanomedicines. To solve these problems, a smart albumin‐based tumor microenvironment‐responsive nanoagent is designed via the self‐assembly of human serum albumin (HSA), dc‐IR825 (a cyanine dye and a photothermal agent), and gambogic acid (GA, a heat shock protein 90 (HSP90) inhibitor and an anticancer agent) to realize molecular targeting‐mediated mild‐temperature PTT. The formed HSA/dc‐IR825/GA nanoparticles (NPs) can escape from mitochondria to the cytosol through mitochondrial disruption under near‐infrared (NIR) laser irradiation. Moreover, the GA molecules block the hyperthermia‐induced overexpression of HSP90, achieving the reduced thermoresistance of tumor cells and effective PTT at a mild temperature (<45 °C). Furthermore, HSA/dc‐IR825/GA NPs show pH‐responsive charge reversal, effective tumor accumulation, and negligible liver deposition, ultimately facilitating synergistic mild‐temperature PTT and chemotherapy. Taken together, the NIR‐activated NPs allow the release of molecular drugs more precisely, ablate tumors more effectively, and inhibit cancer metastasis more persistently, which will advance the development of novel mild‐temperature PTT‐based combination strategies.     

Precise Two‐Photon Photodynamic Therapy using an Efficient Photosensitizer with Aggregation‐Induced Emission Characteristics

Two‐photon photodynamic therapy (PDT) is able to offer precise 3D manipulation of treatment volumes, providing a target level that is unattainable with current therapeutic techniques. The advancement of this technique is greatly hampered by the availability of photosensitizers with large two‐photon absorption (TPA) cross section, high reactive‐oxygen‐species (ROS) generation efficiency, and bright two‐photon fluorescence. Here, an effective photosensitizer with aggregation‐induced emission (AIE) characteristics is synthesized, characterized, and encapsulated into an amphiphilic block copolymer to form organic dots for two‐photon PDT applications. The AIE dots possess large TPA cross section, high ROS generation efficiency, and excellent photostability and biocompatibility, which overcomes the limitations of many conventional two‐photon photosensitizers. Outstanding therapeutic performance of the AIE dots in two‐photon PDT is demonstrated using in vitro cancer cell ablation and in vivo brain‐blood‐vessel closure as examples. This shows therapy precision up to 5 µm under two‐photon excitation.     

Oxidation‐Responsive Nanoassemblies for Light‐Enhanced Gene Therapy

Microenvironment‐responsive supramolecular assemblies have attracted great interest in the biomedical field due to their potential applications in controlled drug release. In this study, oxidation‐responsive supramolecular polycationic assemblies named CPAs are prepared for nucleic acid delivery via the host–guest interaction of β‐cyclodextrin based polycations and a ferrocene‐functionalized zinc tetraaminophthalocyanine core. The reactive oxygen species (ROS) can accelerate the disassembly of CPA/pDNA complexes, which would facilitate the release of pDNA in the complexes and further benefit the subsequent transfection. Such improvement in transfection efficiency is proved in A549 cells with high H₂O₂ concentration. Interestingly, the transfection efficiencies mediated by CPAs are also different in the presence or absence of light in various cell lines such as HEK 293 and 4T1. The single oxygen (¹O₂), produced by photosensitizers in the core of CPAs under light, increases the ROS amount and accelerates the disassembly of CPAs/pDNA complexes. In vitro and in vivo studies further illustrate that suppressor tumor gene p53 delivered by CPAs exhibits great antitumor effects under illumination. This work provides a promising strategy for the design and fabrication of oxidation‐responsive nanoassemblies with light‐enhanced gene transfection performance.     

A Highly‐Efficient Type I Photosensitizer with Robust Vascular‐Disruption Activity for Hypoxic‐and‐Metastatic Tumor Specific Photodynamic Therapy

Hypoxia severely impedes photodynamic therapy (PDT) efficiency. Worse still, considerable tumor metastasis will occur after PDT. Herein, an organic superoxide radical (O₂^??) nano‐photogenerator as a highly effcient type I photosensitizer with robust vascular‐disrupting efficiency to combat these thorny issues is designed. Boron difluoride dipyrromethene (BODIPY)‐vadimezan conjugate (BDPVDA) is synthesized and enwrapped in electron‐rich polymer‐brushes methoxy‐poly(ethylene glycol)‐b‐poly(2‐(diisopropylamino) ethyl methacrylate) (mPEG‐ PPDA) to afford nanosized hydrophilic type I photosensitizer (PBV NPs). Owing to outstanding core–shell intermolecular electron transfer between BDPVDA and mPEG‐PPDA, remarkable O₂^?? can be produced by PBV NPs under near‐infrared irradiation even in severe hypoxic environment (2% O₂), thus to accomplish effective hypoxic‐tumor elimination. Simultaneously, the efficient ester‐bond hydrolysis of BDPVDA in the acidic tumor microenvironment allows vadimezan release from PBV NPs to disrupt vasculature, facilitating the shut‐down of metastatic pathways. As a result, PBV NPs will not only be powerful in resolving the paradox between traditional type II PDT and hypoxia, but also successfully prevent tumor metastasis after type I PDT treatment (no secondary‐tumors found in 70 days and 100% survival rate), enabling enhancement of existing hypoxic‐and‐metastatic tumor treatment.     

Multifunctional Mesoporous Silica Nanoparticles with Thermal‐Responsive Gatekeeper for NIR Light‐Triggered Chemo/Photothermal‐Therapy

In this work, a matrix metalloproteinase (MMP)‐triggered tumor targeted mesoporous silica nanoparticle (MSN) is designed to realize near‐infrared (NIR) photothermal‐responsive drug release and combined chemo/photothermal tumor therapy. Indocyanine green (ICG) and doxorubicin (DOX) are both loaded in the MSN modified with thermal‐cleavable gatekeeper (Azo‐CD), which can be decapped by ICG‐generated hyperthermia under NIR illumination. A peptidic sequence containing a short PEG chain, matrix metalloproteinase (MMP) substrate (PLGVR) and tumor cell targeting motif (RGD) are further decorated on the MSN via a host–guest interaction. The PEG chain can protect the MSN during the circulation and be cleaved off in the tumor tissues with overexpressed MMP, and then the RGD motif is switched on to target tumor cells. After the tumor‐triggered targeting process, the NIR irradiation guided by ICG fluorescence can trigger cytosol drug release and realize combined chemo/photothermal therapy.     

A Highly Efficient and Photostable Photosensitizer with Near‐Infrared Aggregation‐Induced Emission for Image‐Guided Photodynamic Anticancer Therapy

Photodynamic therapy (PDT), which relies on photosensitizers (PS) and light to generate reactive oxygen species to kill cancer cells or bacteria, has attracted much attention in recent years. PSs with both bright emission and efficient singlet oxygen generation have also been used for image‐guided PDT. However, simultaneously achieving effective ¹O₂ generation, long wavelength absorption, and stable near‐infrared (NIR) emission with low dark toxicity in a single PS remains challenging. In addition, it is well known that when traditional PSs are made into nanoparticles, they encounter quenched fluorescence and reduced ¹O₂ production. In this contribution, these challenging issues have been successfully addressed through designing the first photostable photosensitizer with aggregation‐induced NIR emission and very effective ¹O₂ generation in aggregate state. The yielded nanoparticles show very effective ¹O₂ generation, bright NIR fluorescence centered at 820 nm, excellent photostability, good biocompatibility, and negligible dark in vivo toxicity. Both in vitro and in vivo experiments prove that the nanoparticles are excellent candidates for image‐guided photodynamic anticancer therapy.     

NIR‐Responsive Polycationic Gatekeeper‐Cloaked Hetero‐Nanoparticles for Multimodal Imaging‐Guided Triple‐Combination Therapy of Cancer

Responsive multifunctional organic/inorganic nanohybrids are promising for effective and precise imaging‐guided therapy of cancer. In this work, a near‐infrared (NIR)‐triggered multifunctional nanoplatform comprising Au nanorods (Au NRs), mesoporous silica, quantum dots (QDs), and two‐armed ethanolamine‐modified poly(glycidyl methacrylate) with cyclodextrin cores (denoted as CD‐PGEA) has been successfully fabricated for multimodal imaging‐guided triple‐combination treatment of cancer. A hierarchical hetero‐structure is first constructed via integration of Au NRs with QDs through a mesoporous silica intermediate layer. The X‐ray opacity and photoacoustic (PA) property of Au NRs are utilized for tomography (CT) and PA imaging, and the imaging sensitivity is further enhanced by the fluorescent QDs. The mesoporous feature of silica allows the loading of a typical antitumor drug, doxorubicin (DOX), which are sealed by the polycationic gatekeepers, low toxic hydroxyl‐rich CD‐PGEA/pDNA complexes, realizing the co‐delivery of drug and gene. The photothermal effect of Au NRs is utilized for photothermal therapy (PTT). More interestingly, such photothermal effect also induces a cascade of NIR‐triggered release of DOX through the facilitated detachment of CD‐PGEA gatekeepers for controlled chemotherapy. The resultant chemotherapy and gene therapy for glioma tumors are complementary for the efficiency of PTT. This work presents a novel responsive multifunctional imaging‐guided therapy platform, which combines fluorescent/PA/CT imaging and gene/chemo/photothermal therapy into one nanostructure.     

Supramolecular Protein Nanodrugs with Coordination‐ and Heating‐Enhanced Photothermal Effects for Antitumor Therapy

Supramolecular protein nanodrugs provide opportunities for improving antitumor therapeutic efficiency and lowering toxicity. However, protein nanodrugs that have robust structural stability and enhanced therapeutic efficiency are still in infancy. In this study, photothermal protein nanodrugs are constructed through a supramolecular approach along with heating by using proteins, photosensitizers, and metal ions as the building blocks. The metal coordination and heating improve not only the structural stability but also photothermal performance of the resulting nanodrugs. By virtue of the first integration of coordination‐ and heating‐enhanced photothermal effects, the nanodrugs show superior photothermal conversion efficiency, enhanced tumor accumulation, and improved tumor inhibition. Metal coordination and heating are versatile to be applied for various protein nanodrugs. Hence, this study provides insights for the construction of highly efficient photothermal nanodrugs and thus will be beneficial to precision theranostics.     

Fluorescent Imaging‐Guided Chemotherapy‐and‐Photodynamic Dual Therapy with Nanoscale Porphyrin Metal–Organic Framework

Imaging‐guided therapy systems (IGTSs) are revolutionary techniques used in cancer treatment due to their safety and efficiency. IGTSs should have tunable compositions for bioimaging, a suitable size and shape for biotransfer, sufficient channels and/or pores for drug loading, and intrinsic biocompatibility. Here, a biocompatible nanoscale zirconium‐porphyrin metal–organic framework (NPMOF)‐based IGTS that is prepared using a microemulsion strategy and carefully tuned reaction conditions is reported. A high content of porphyrin (59.8%) allows the achievement of efficient fluorescent imaging and photodynamic therapy (PDT). The 1D channel of the Kagome topology of NPMOFs provides a 109% doxorubicin loading and pH‐response smart release for chemotherapy. The fluorescence guiding of the chemotherapy‐and‐PDT dual system is confirmed by the concentration of NPMOFs at cancer sites after irradiation with a laser and doxorubicin release, while low toxicity is observed in normal tissues. NPMOFs are established as a promising platform for the early diagnosis of cancer and initial therapy.     

Rhenium‐188 Labeled Tungsten Disulfide Nanoflakes for Self‐Sensitized,Near‐Infrared Enhanced Radioisotope Therapy

Radioisotope therapy (RIT), in which radioactive agents are administered or implanted into the body to irradiate tumors from the inside, is a clinically adopted cancer treatment method but still needs improvement to enhance its performances. Herein, it is found that polyethylene glycol (PEG) modified tungsten disulfide (WS₂) nanoflakes can be easily labeled by ¹⁸⁸Re, a widely used radioisotope for RIT, upon simple mixing. Like other high‐Z elements acting as radiosensitizers, tungsten in the obtained ¹⁸⁸Re‐WS₂‐PEG would be able to absorb ionization radiation generated from ¹⁸⁸Re, enabling ‘‘self‐sensitization’’ to enhance the efficacy of RIT as demonstrated in carefully designed in vitro experiments of this study. In the meanwhile, the strong NIR absorbance of WS₂‐PEG could be utilized for NIR light‐induced photothermal therapy (PTT), which if applied on tumors would be able to greatly relieve their hypoxia state and help to overcome hypoxia‐associated radioresistance of tumors. Therefore, with ¹⁸⁸Re‐WS₂‐PEG as a multifunctional agent, which shows efficient passive tumor homing after intravenous injection, in vivo self‐sensitized, NIR‐enhanced RIT cancer treatment is realized, achieving excellent tumor killing efficacy in a mouse tumor model. This work presents a new concept of applying nanotechnology in RIT, by delivering radioisotopes into tumors, self‐sensitizing the irradiation‐induced cell damage, and modulating the tumor hypoxia state to further enhance the therapeutic outcomes.     

Smart Carbon Nanotubes with Laser‐Controlled Behavior in Gene Delivery and Therapy through a Non‐Digestive Trafficking Pathway

Near‐infrared (NIR) laser‐controlled gene delivery presents some benefits in gene therapy, inducing enhanced gene transfection efficiency. In this study, a “photothermal transfection” agent is obtained by wrapping poly(ethylenimine)‐cholesterol derivatives (PEI‐Chol) around single‐walled carbon nanotubes (SWNTs). The PEI‐Chol modified SWNTs (PCS) are effective in compressing DNA molecules and protecting them from DNaseI degradation. Compared to the complexes formed by PEI with DNA (PEI/DNA), complexes of PCS and DNA that are formed (PCS/DNA) exhibit a little lower toxicity to HEK293 and HeLa cells under the same PEI molecule weight and weight ratios. Notably, caveolae‐mediated cellular uptake of PCS/DNA occurs, which results in a safer intracellular transport of the gene due to the decreased lysosomal degradation in comparison with that of PEI/DNA whose internalization mainly depends on clathrin rather than caveolae. Furthermore, unlike PEI/DNA, PCS/DNA exhibits a photothermal conversion ability, which promotes DNA release from PCS under NIR laser irradiation. The NIR laser‐mediated photothermal transfection of PCS_10K/plasmid TP53 (pTP53) results in more apoptosis and necrosis of HeLa cells in vitro than other groups, and achieves a higher tumor‐growth inhibition in vivo than naked pTP53, PEI_25K/pTP53, and PCS_10K/pTP53 alone. The enhanced transfection efficiency of PCS/DNA can be attributed to more efficient DNA internalization into the tumor cells, promotes detachment of DNA from PCS under the mediation of NIR laser and higher DNA stability in the cells due to caveolae‐mediated cellular uptake of the complexes.     

Self‐Assembled Aptamer‐Nanomedicine for Targeted Chemotherapy and Gene Therapy

Chemotherapy is the mainstream treatment of anaplastic large cell lymphoma (ALCL). However, chemotherapy can cause severe adverse effects in patients because it is not ALCL‐specific. In this study, a multifunctional aptamer‐nanomedicine (Apt‐NMed) achieving targeted chemotherapy and gene therapy of ALCL is developed. Apt‐NMed is formulated by self‐assembly of synthetic oligonucleotides containing CD30‐specific aptamer and anaplastic lymphoma kinase (ALK)‐specific siRNA followed by self‐loading of the chemotherapeutic drug doxorubicin (DOX). Apt‐NMed exhibits a well‐defined nanostructure (diameter 59 mm) and stability in human serum. Under aptamer guidance, Apt‐NMed specifically binds and internalizes targeted ALCL cells. Intracellular delivery of Apt‐NMed triggers rapid DOX release for targeted ALCL chemotherapy and intracellular delivery of the ALK‐specific siRNA induced ALK oncogene silencing, resulting in combined therapeutic effects. Animal model studies reveal that upon systemic administration, Apt‐NMed specifically targets and selectively accumulates in ALCL tumor site, but does not react with off‐target tumors in the same xenograft mouse. Importantly, Apt‐NMed not only induces significantly higher inhibition in ALCL tumor growth, but also causes fewer or no side effects in treated mice compared to free DOX. Moreover, Apt‐NMed treatment markedly improves the survival rate of treated mice, opening a new avenue for precision treatment of ALCL.     

DNA‐Assembled Core‐Satellite Upconverting‐Metal–Organic Framework Nanoparticle Superstructures for Efficient Photodynamic Therapy

DNA‐mediated assembly of core–satellite structures composed of Zr(IV)‐based porphyrinic metal‐organic framework (MOF) and NaYF₄,Yb,Er upconverting nanoparticles (UCNPs) for photodynamic therapy (PDT) is reported. MOF NPs generate singlet oxygen (¹O₂) upon photoirradiation with visible light without the need for additional small molecule, diffusional photosensitizers such as porphyrins. Using DNA as a templating agent, well‐defined MOF–UCNP clusters are produced where UCNPs are spatially organized around a centrally located MOF NP. Under NIR irradiation, visible light emitted from the UCNPs is absorbed by the core MOF NP to produce ¹O₂ at significantly greater amounts than what can be produced from simply mixing UCNPs and MOF NPs. The MOF–UCNP core–satellite superstructures also induce strong cell cytotoxicity against cancer cells, which are further enhanced by attaching epidermal growth factor receptor targeting affibodies to the PDT clusters, highlighting their promise as theranostic photodynamic agents.