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.     

Persistent Regulation of Tumor Microenvironment via Circulating Catalysis of MnFe2O4@Metal–Organic Frameworks for Enhanced Photodynamic Therapy

Reactive oxygen species (ROS)‐based cancer therapy, such as photodynamic therapy (PDT), is subject to the hypoxia and overexpressed glutathione (GSH) found in the tumor microenvironment (TME). Herein, a novel strategy is reported to continuously and simultaneously regulate tumor hypoxia and reducibility in order to achieve the desired therapeutic effect. To accomplish this, a biocompatible nanoplatform (MnFe₂O₄@metal–organic framework (MOF)) is developed by integrating a coating of porphyrin‐based MOF as the photosensitizer and manganese ferrite nanoparticle (MnFe₂O₄) as the nanoenzyme. The synthetic MnFe₂O₄@MOF nanoplatform exhibits both catalase‐like and glutathione peroxidase‐like activities. Once internalized in the tumor, the nanoplatform can continuously catalyze H₂O₂ to produce O₂ to overcome the tumor hypoxia by cyclic Fenton reaction. Meanwhile, combined with the Fenton reaction, MnFe₂O₄@MOF is able to persistently consume GSH in the presence of H₂O₂, which decreases the depletion of ROS upon laser irradiation during PDT and achieves better therapeutic efficacy in vitro and in vivo. Moreover, the nanoplatform integrates a treatment modality with magnetic resonance imaging, along with persistent regulation of TME, to promote more precise and effective treatment for future clinical application.     

Copper(I) Phosphide Nanocrystals for In Situ Self‐Generation Magnetic Resonance Imaging‐Guided Photothermal‐Enhanced Chemodynamic Synergetic Therapy Resisting Deep‐Seated Tumor

Fe‐based Fenton agents can generate highly reactive and toxic hydroxyl radicals (·OH) in the tumor microenvironment (TME) for chemodynamic therapy (CDT) with high specificity. However, the strict condition (lower pH environment: 3–4) of the highly efficient Fenton reaction limits its practical application in the clinic. Development of new CDT agents more suitable for TME is significant and challenging. A highly efficient Cu(I)‐based CDT agent, copper(I) phosphide nanocrystals (CP NCs), which is more adaptable to the pH value of TME than Fe‐based agents, thereby producing more ·OH to trigger the apoptosis of cancer cells, is prepared. Moreover, the excess glutathione (GSH) in TME can reduce the Cu(II) produced by a Fenton‐like reaction to Cu(I), further increasing the generation rate of ·OH and relieving tumor antioxidant ability. Furthermore, owing to their strong absorption in the NIR II region, CP NCs exhibit an excellent photothermal conversion effect, which can further improve the Fenton reaction. What is more, CP NCs can act as in situ self‐generation magnetic resonance imaging (MRI) agents owing to the generation of paramagnetic Cu(II) in response to excess H₂O₂ in the TME. These properties may open up the exploration of copper‐based materials in clinical application of self‐generation imaging‐guided synergetic treatment.     

Smart Tumor Microenvironment‐Responsive Nanotheranostic Agent for Effective Cancer Therapy

The tumor microenvironment (TME), which includes acidic and hypoxic conditions, severely impedes the therapeutic efficacy of antitumor agents. Herein, MnO₂‐loaded, bovine serum albumin, and PEG co‐modified mesoporous CaSiO₃ nanoparticles (CaM‐PB NPs) are developed as a nanoplatform with sequential theranostic functions for the engineering of TME. The MnO₂ NPs generate O₂ in situ by reacting with endogenous H₂O₂, relieving the hypoxic state of the TME that further modulates the cancer cell cycle status to S phase, which improves the potency of co‐loaded S phase‐sensitive chemotherapeutic drugs. After the hypoxia relief, CaM‐PB can sustainably release drugs due to the enlarged pores of mesoporous CaSiO₃ in the acidic TME, preventing the drug pre‐leakage into the blood circulation and insufficient drug accumulation at tumor sites. Moreover, the Mn²⁺ released from the MnO₂ NPs at tumor sites can potentially serve as a diagnostic agent, enabling the identification of tumor regions by T₁‐weighted magnetic resonance imaging during therapy. In vivo pharmacodynamics results demonstrate that these synergetic effects caused by CaM‐PB NPs significantly contribute to the inhibition of tumor progression. Therefore, the CaM‐PB NPs with sequential theranostic functions are a promising system for effective cancer therapy.     

Hyaluronidase with pH‐responsive Dextran Modification as an Adjuvant Nanomedicine for Enhanced Photodynamic‐Immunotherapy of Cancer

The condensed tumor extracellular matrix (ECM) consisting of cross‐linked hyaluronic acid (HA) is one of key factors that results in the aberrant tumor microenvironment (TME) and the resistance to various types of therapies. Herein, hyaluronidase (HAase) is modified by a biocompatible polymer, dextran (DEX), via a pH‐responsive traceless linker. The formulated DEX‐HAase nanoparticles show enhanced enzyme stability, reduced immunogenicity, and prolonged blood half‐life after intravenous injection. With efficient tumor passive accumulation, DEX‐HAase within the acidic TME would be dissociated to release native HAase, which afterward triggers the breakdown of HA to loosen the ECM structure, subsequently leading to enhanced penetration of oxygen and other therapeutic agents. The largely relieved tumor hypoxia would promote the therapeutic effect of nanoparticle‐based photodynamic therapy (PDT), accompanied by the reverse of the immunosuppressive TME to boost cancer immunotherapy. Interestingly, the therapeutic responses achieved by the combination of PDT and anti‐programmed death‐ligand 1 (anti‐PD‐L1) checkpoint blockade therapy could be significantly enhanced by pretreatment with DEX‐HAase. In addition to destructing tumors with direct light exposure, a robust abscopal effect is achieved after such treatment, which is promising for tumor metastasis inhibition. The work presents a new type of adjuvant nanomedicine to assist photodynamic‐immunotherapy of cancer, by effective modulation of TME.     

Light‐Responsive,Singlet‐Oxygen‐Triggered On‐Demand Drug Release from Photosensitizer‐Doped Mesoporous Silica Nanorods for Cancer Combination Therapy

Smart drug delivery systems with on‐demand drug release capability are rather attractive to realize highly specific cancer treatment. Herein, a novel light‐responsive drug delivery platform based on photosensitizer chlorin e6 (Ce6) doped mesoporous silica nanorods (CMSNRs) is developed for on‐demand light‐triggered drug release. In this design, CMSNRs are coated with bovine serum albumin (BSA) via a singlet oxygen (SO)‐sensitive bis‐(alkylthio)alkene (BATA) linker, and then modified with polyethylene glycol (PEG). The obtained CMSNR‐BATA‐BSA‐PEG, namely CMSNR‐B‐PEG, could act as a drug delivery carrier to load with either small drug molecules such as doxorubicin (DOX), or larger macromolecules such as cis‐Pt (IV) pre‐drug conjugated third generation dendrimer (G3‐Pt), both of which are sealed inside the mesoporous structure of nanorods by BSA coating. Upon 660 nm light irradiation with a rather low power density, CMSNRs with intrinsic Ce6 doping would generate SO to cleave BATA linker, inducing detachment of BSA‐PEG from the nanorod surface and thus triggering release of loaded DOX or G3‐Pt. As evidenced by both in vitro and in vivo experiments, such CMSNR‐B‐PEG with either DOX or G3‐Pt loading offers remarkable synergistic therapeutic effects in cancer treatment, owing to the on‐demand release of therapeutics specifically in the tumor under light irradiation.     

Unprecedented Theranostic LaB6 Nanocubes‐Mediated NIR‐IIb Photodynamic Therapy to Conquer Hypoxia‐Induced Chemoresistance

Tumor hypoxia and chemoresistance are long‐lasting challenges in clinical cancer treatments resulting in treatment failures and low patient survival rates. Application of phototherapies to treat deep tissue‐buried tumors has been hampered by the lack of near infrared photosensitizers, and consumption of tissue oxygen, worsening the tumor hypoxia problem. Herein, an unprecedented theranostic lanthanum hexaboride‐based nanodrug is engineered to act as bimodal computed tomographic/magnetic resonance imaging contrast agents, absorb long near infrared (NIR) light in the biological window IIb (1500–1700 nm), generate hydroxyl radicals without using oxygen, and destroy drug‐resistant NCI‐H23 lung tumors completely, leading to an amazingly long average half‐life of 180 days, far exceeding than those of doxorubicin‐treated (21 days) and untreated mice groups (13 days). This work pioneers the field of photodynamic therapy in conquering hypoxia and chemodrug resistance problems for NIR‐IIb oxygen‐independent cancer treatments.     

A Triple‐Collaborative Strategy for High‐Performance Tumor Therapy by Multifunctional Mesoporous Silica‐Coated Gold Nanorods

To integrate treatments of photothermal therapy, photodynamic therapy (PDT), and chemotherapy, this study reports on a multifunctional nanocomposite based on mesoporous silica‐coated gold nanorod for high‐performance oncotherapy. Gold nanorod core is used as the hyperthermal agent and mesoporous silica shell is used as the reservoir of photosensitizer (Al(III) phthalocyanine chloride tetrasulfonic acid, AlPcS₄). The mesoporous silica shell is modified with β‐cyclodextrin (β‐CD) gatekeeper via redox‐cleavable Pt(IV) complex for controlled drug release. Furthermore, tumor targeting ligand (lactobionic acid, LA) and long‐circulating poly(ethylene glycol) chain are introduced via host–guest interaction. It is found that the nanocomposite can specifically target to hepatoma cells by virtue of the LA targeting moiety. Due to the abundant existence of reducing agents within tumor cells, β‐CD can be removed by reducing the Pt(IV) complex to active cisplatin drug for chemotherapy, along with the releasing of entrapped AlPcS₄ for effective PDT. As confirmed by in vitro and in vivo studies, the nanocomposite exhibits an obvious near‐infrared induced thermal effect, which significantly improves the PDT and chemotherapy efficiency, resulting in a superadditive therapeutic effect. This collaborative strategy paves the way toward high‐performance nanotherapeutics with a superior antitumor efficacy and much reduced side effects.     

Tumor-Activated Photosensitization and Size Transformation of Nanodrugs

Effective intratumoral distribution of anticancer agents with good tumor penetration is of practical importance for photo-chemotherapy. Herein, a metal-organic framework (MOF) assisted strategy is reported for smart delivery of aggregation-induced emission photosensitizer (AIE PS) and chemodrug for deep tumor penetration to realize effective image-guided photo-chemotherapy. A newly designed AIE PS is loaded inside an iron(III) carboxylate-based MOF, MIL-100, to produce PS@MIL-100, which is encapsulated by doxorubicin (Dox) conjugated poly(ethylene glycol) methyl ether (PEG) to yield Dox-PEG-PS@MIL nanoparticles (NPs) with a diameter of 120 nm. After Dox-PEG-PS@MIL NPs reached the tumor site, intratumoral H₂O₂ can cause the release of the loaded PS at the tumor surface for activatable photodynamic therapy (PDT). The Dox-PEG segment is simultaneously triggered to self-assemble into ultrasmall Dox NPs. Under light irradiation, PDT is activated at the tumor surface, synergistically enhancing the tumor penetration of Dox NPs along with their ultrasmall size. After endocytosis of Dox NPs, free Dox is released from Dox NPs under low pH to enter cell nuclei for effective chemotherapy. Accompanied by bright far-red/near-infrared emission from the PS, image-guided photo-chemotherapy with enhanced efficacy is achieved.     

Nanoscale‐Coordination‐Polymer‐Shelled Manganese Dioxide Composite Nanoparticles: A Multistage Redox/pH/H2O2‐Responsive Cancer Theranostic Nanoplatform

Nanoscale coordination polymers (NCPs) self‐assembled from metal ions and organic bridging ligands exhibit many unique features promising for applications in nanomedicine. In this work, manganese dioxide (MnO₂) nanoparticles stabilized by bovine serum albumin are encapsulated by NCP‐shells constructed based on high‐Z element hafnium (Hf) ions and c,c,t‐(diamminedichlorodisuccinato)Pt(IV) (DSP), a cisplatin prodrug. After further modification with polyethylene glycol (PEG), the formed BM@NCP(DSP)‐PEG can simultaneously serve as a radio‐sensitizer owing to the strong X‐ray attenuation capability of Hf to enhance radiotherapy, as well as a chemotherapeutic agent resulting from the reduction‐induced release of cisplatin. Meanwhile, the in situ generated oxygen resulting from MnO₂‐triggered decomposition of tumor endogenous H₂O₂ will be greatly helpful for overcoming hypoxia‐associated radio‐resistance. Upon intravenous injection, BM@NCP(DSP)‐PEG shows efficient tumor homing as well as rapid renal excretion, as illustrated by magnetic resonance imaging and confirmed by biodistribution measurement. Notably, an excellent in vivo tumor growth inhibition effect is observed with BM@NCP(DSP)‐PEG nanoparticles after the combined chemoradiotherapy treatment. Therefore, the NCP‐based composite nanoparticles with inherent biodegradability and no appreciable in vivo toxicity may be a unique type of multifunctional nanoplatform responsive to different parameters in the tumor microenvironment, promising for cancer theranostics with great efficacy.     

A Versatile Prodrug Strategy to In Situ Encapsulate Drugs in MOF Nanocarriers: A Case of Cytarabine‐IR820 Prodrug Encapsulated ZIF‐8 toward Chemo‐Photothermal Therapy

Zeolitic imidazolate framework‐8 (ZIF‐8) is an attractive metal organic framework (MOF) in drug delivery. Strong interaction between drugs and ZIF‐8 is essential for high drug loadings through in situ construction of MOFs. However, only limited drugs with unique functional groups (? COOH, ? SO₃H, et al.) can interact with ZIF‐8 and be encapsulated satisfactorily so far. Drugs without these functional groups are difficult to be loaded due to the lack of strong interaction. Herein a versatile prodrug strategy is proposed to solve the problems encountered by MOFs. Cytarabine (Ara) is chosen as a model drug since it cannot be loaded in ZIF‐8 satisfactorily by itself. New indocyanine green (IR820) is utilized to bond with Ara for the formation of prodrug (Ara‐IR820) and endows the prodrug with fluorescence imaging‐guided chemo‐photothermal therapy, in which sulfonic groups strengthen the interaction between prodrug and ZIF‐8. This prodrug loaded ZIF‐8 is further functionalized with hyaluronic acid (HA) to result in active‐targeting HA/Ara‐IR820@ZIF‐8 nanoparticles. The in vitro and in vivo results demonstrate its excellent visual cancer therapy with tumor‐targeted and pH‐responsive release behavior. This design offers a new concept to solve the drug loading problem of MOFs, exhibiting a flexible strategy to expand the biomedical applications of MOFs.     

Design of Hybrid MnO2‐Polymer‐Lipid Nanoparticles with Tunable Oxygen Generation Rates and Tumor Accumulation for Cancer Treatment

Manganese dioxide (MnO₂) nanoparticles (NPs) were discovered in previous work to be effective in improving tumor oxygenation (hypoxia) and reducing H₂O₂ and acidity in the tumor microenvironment (TME) via local injection. To develop MnO₂ formulations useful for clinical application, hybrid NPs are designed with tailored hydrophobicity and structure suitable for intravenous injection, with good blood circulation, biocompatibility, high tumor accumulation, and programmable oxygen generation rate. Two different hybrid NPs are constructed by embedding polyelectrolyte‐MnO₂ (PMD) in hydrophilic terpolymer/protein‐MnO₂ (TMD) or hydrophobic polymer/lipid‐MnO₂ (LMD) matrices. The in vitro reactivity of the MnO₂ toward H₂O₂ is controlled by matrix material and NP structure and dependent on pH with up to two‐fold higher O₂ generation rate at acidic (tumor) pH than at systemic pH. The hybrid NPs are found to be safe to cells in vitro and organs in vivo and effectively decrease tumor hypoxia and hypoxia‐inducible‐factor‐1alpha through local or systemic administration. Fast acting TMD reduces tumor hypoxia by 70% in 0.5 h by local injection. Slow acting LMD exhibits superior tumor accumulation and retention through the systemic administration and decreased hypoxia by 45%. These findings encourage a broader use of hybrid MD NPs to overcome TME factors for cancer treatment.     

Oxygen‐Generating MnO2 Nanodots‐Anchored Versatile Nanoplatform for Combined Chemo‐Photodynamic Therapy in Hypoxic Cancer

Local hypoxia in tumors results in undesirable impediments for the efficiencies of oxygen‐dependent chemical and photodynamic therapy (PDT). Herein, a versatile oxygen‐generating and pH‐responsive nanoplatform is developed by loading MnO₂ nanodots onto the nanosystem that encapsulates g‐C₃N₄ and doxorubicin hydrochloride to overcome the hypoxia‐caused resistance in cancer therapy. The loaded MnO₂ nanodots can react with endogenous acidic H₂O₂ to elevate the dissolved oxygen concentration, leading to considerably enhanced cancer therapy efficacy. As such, the as‐prepared nanoplatform with excellent dispersibility and satisfactory biocompatibility can sustainably increase the oxygen concentration and rapidly release the encapsulated drugs in acid H₂O₂ environment. In vitro cytotoxicity experiments show a higher therapy effect by the designed nanoplatform, when compared to therapy without MnO₂ nanodots under hypoxia condition, or chemical and photodynamic therapy alone with the presence of MnO₂ nanodots. In vivo experiments also demonstrate that 4T1 tumors can be very efficiently eliminated by the designed nanoplatform under light irradiation. These results highlight that the MnO₂ nanodots‐based nanoplatform is promising for elevating the oxygen level in tumor microenvironments to overcome hypoxia limitations for high‐performance cancer therapy.     

Long‐Term Oxygen Storage Nanosystem for Near‐Infrared Light‐Triggered Oxygen Supplies to Antagonize Hypoxia‐Induced Therapeutic Resistance in Nasopharyngeal Carcinoma

O₂‐delivering nanosystems have been used to antagonize hypoxia‐induced tumor therapeutic resistance. However, short‐time oxygen storage is still a bottleneck for these O₂‐delivering nanosystems, which results in a decrease in blood circulation time and accumulation of oxygen in tumors, thus reducing the tumor therapeutic efficacy. Herein, a long‐term oxygen storage nanosystem (O₂‐PIr@Si@PDA) is designed to overcome hypoxia for the treatment of nasopharyngeal carcinoma. This nanosystem is constructed by using perfluorooctyl bromide (PFOB) core as the oxygen carrier, functionalized with an oxygen sensitive probe (Ir(III) complex) and subsequently enclosed with an ultrathin‐walled silica shell. Due to the silica shell, this nanosystem can store oxygen for longer than 7 days. The oxygen in the O₂‐PIr@Si@PDA nanosystem can be released quickly with the temperature‐responsive rupture of the silicon shell under near‐infrared (NIR) irradiation. The oxygen storage and release can be self‐monitored using the Ir(III) complex with its luminescence effect. As expected, this multifunctional nanosystem in combination with NIR irradiation not only inhibits tumor growth by alleviating hypoxia, but also enhances the effect of oxygen‐sensitized radiotherapy against nasopharyngeal carcinoma. Taken together, this study offers a novel strategy for designing long‐term oxygen storing nanosystem to relieve tumor hypoxia, thus improving the precise cancer therapeutic efficacy.     

Glutathione‐Activatable and O2/Mn2+‐Evolving Nanocomposite for Highly Efficient and Selective Photodynamic and Gene‐Silencing Dual Therapy

Photodynamic therapy (PDT) has been applied in cancer treatment by converting O₂ into reactive singlet oxygen (¹O₂) to kill cancer cells. However, the effectiveness of PDT is limited by the fact that tumor hypoxia causes an inadequate O₂ supply, and the overexpressed glutathione (GSH) in cancer cells consumes reactive oxygen species. Herein, a multifunctional hybrid system is developed for selective and highly efficient PDT as well as gene‐silencing therapy using a novel GSH‐activatable and O₂/Mn²⁺‐evolving nanocomposite (GAOME NC). This system consists of honeycomb MnO₂ (hMnO₂) nanocarrier loaded with catalase, Ce6, and DNAzyme with folate label, which can specifically deliver payloads into cancer cells. Once endocytosed, hMnO₂ carriers are reduced by the overexpressed GSH to Mn²⁺ ions, resulting in the reduction of GSH level and disintegration of GAOME NC. The released catalases then trigger the breakdown of endogenous H₂O₂ to generate O₂, which is converted by the excited Ce6 into ¹O₂. The self‐sufficiency of O₂ and consumption of GSH effectively enhance the PDT efficacy. Moreover, DNAzyme is freed for gene silencing in the presence of self‐generated Mn²⁺ ions as cofactors. The rational synergy of enhanced PDT and gene‐silencing therapy remarkably improve the in vitro and in vivo therapeutic efficacy of cancers.     

Targeted Tumor Hypoxia Dual‐Mode CT/MR Imaging and Enhanced Radiation Therapy Using Dendrimer‐Based Nanosensitizers

The efficacy of radiation therapy (RT) is often limited by the poor response of hypoxia inside most solid tumors. The development of a theranostic nanoplatform for precision‐imaging‐guided sensitized RT for tumor hypoxia is still challenging. Herein, the creation of hypoxia‐targeted dendrimer‐entrapped gold nanoparticles complexed with gadolinium(III) (Gd‐Au DENPs‐Nit) for dual‐mode CT/MR imaging and sensitized RT of hypoxic tumors is reported. In this work, generation 5 poly(amidoamine) dendrimers are partially conjugated with Gd(III) chelator, entrapped with Au nanoparticles, and conjugated with hypoxia‐targeting agent nitroimidazole via a polyethylene glycol linker, and ending with chelation of Gd(III) and conversion of their leftover amine termini to acetamides. The designed dendrimer‐based nanohybrids with 3.2 nm Au cores exhibit an excellent X‐ray attenuation effect, acceptable r₁ relaxivity (1.32 mM^?1 s^?1), and enhanced cellular uptake in hypoxic cancer cells, affording efficient dual‐mode CT/MR imaging of tumor hypoxia. Under X‐ray irradiation, the Gd‐Au DENPs‐Nit nanohybrids can produce reactive oxygen species, promote DNA damage, and prevent DNA repair, facilitating sensitized RT of hypoxic cancer cells in vitro and tumor hypoxia in vivo. The developed hypoxia‐targeted dendrimer‐based nanohybrids may be employed as both contrast agents and nanosensitizers for precision tumor hypoxia imaging and sensitized tumor RT.     

Mesoporous Silica Coated Single‐Walled Carbon Nanotubes as a Multifunctional Light‐Responsive Platform for Cancer Combination Therapy

The development of cancer combination therapies, many of which rely on nanoscale theranostic agents, has received increasing attention in recent years. In this work, polyethylene glycol (PEG) modified mesoporous silica (MS) coated single‐walled carbon nanotubes (SWNTs) are fabricated and utilized as a multifunctional platform for imaging guided combination therapy of cancer. A model chemotherapy drug, doxorubicin (DOX), could be loaded into the mesoporous structure of the obtained SWNT@MS‐PEG nano‐carriers with high efficiency. Upon stimulation under near‐infrared (NIR) light, photothermally triggered drug release from DOX loaded SWNT@MS‐PEG is observed inside cells, resulting in a synergistic cancer cell killing effect. As revealed by both photoacoustic (PA) and magnetic resonance (MR) imaging, we further uncover efficient tumor accumulation of SWNT@MS‐PEG/DOX after intravenous injection into mice. In vivo combination therapy using this agent is further demonstrated in a mouse tumor model, achieving a remarkable synergistic anti‐tumor effect superior to that obtained by mono‐therapy. Our work presents a new type of theranostic nano‐platform, which could load therapeutic molecules with high efficiency, be responsive to external NIR stimulation, and at the same time serve as a diagnostic imaging agent.     

Photoactive Hybrid AuNR‐Pt@Ag2S Core–Satellite Nanostructures for Near‐Infrared Quantitive Cell Imaging

The quantitative detection of microRNA (miR) and multimode‐imaging‐induced photothermal therapy in vivo have become the focus of much attention. Platinum (Pt) decorated gold nanorods (AuNR‐Pt) and Ag₂S core–satellite (AuNR‐Pt@Ag₂S) multifunctional nanostructures are fabricated to quantify intracellular miRs (miR‐21), near‐infrared fluorescence cell quantitative imaging, and tumor ablation in vivo. When combined with miR‐21, the nanoassembly displays significant fluorescence intensity in the second window of the near‐infrared region (1000–1700 nm) after 808 nm excitation. The Ag₂S fluorescence intensity has a good linear relationship with the amount of intracellular miR in the range of 0.054–20.45 amol ng_RNA ^?1 and a limit of detection of 0.0082 amol ng_RNA ^?1. The nanoassembly is also used to develop multimodal bioimaging, including near‐infrared, X‐ray computed tomographic, and photoacoustic imaging in HeLa‐tumor‐bearing mice. Moreover, the tumors are completely eliminated by the high photothermal capacity of the AuNR‐Pt@Ag₂S assembly. This nanoassembly provides a multifunctional nanoplatform for the ultrasensitive detection of miRs and tumor diagnosis and therapy in vivo.     

Intracellular Microenvironment‐Responsive Dendrimer‐Like Mesoporous Nanohybrids for Traceable,Effective, and Safe Gene Delivery

In order to create advanced functional nanocarriers for efficient gene therapy, novel intracellular microenvironment‐sensitive fluorescence label‐free nanostructured dendrimer‐like silica hybrid nanocarriers are developed for traceable, effective, and safe gene delivery. Dendrimer‐like mesoporous silica nanoparticles (DMSNs) with center‐radial large pores are covalently modified with short polyethyleneimine (PEI) for efficient gene loading and binding. Autofluorescent and biodegradable PEI (AC‐PEI) responsive to the intracellular microenvironment are then coated on the gene‐loaded nanoparticles for inhibiting gene leakage from the carriers. Moreover, AC‐PEI coating not only endows intracellular microenvironment‐responsive gene release property, but also allows monitoring the gene delivery process in the absence of external labelling, owing to the pH‐ and GSH‐responsive autofluorescence and biodegradability of AC‐PEI. The resultant nanocarriers show high gene loading capacity, low cytotoxicity, stimuli‐responsive gene release, label‐free, and simultaneous fluorescence tracking, and high gene silencing capability. Thus, these developed nanocarriers hold substantial and promising potential as effective and safe gene‐delivery carriers for future scientific investigation and practical implications in gene therapy.     

SnTe@MnO2‐SP Nanosheet–Based Intelligent Nanoplatform for Second Near‐Infrared Light–Mediated Cancer Theranostics

Near infrared light, especially the second near‐infrared light (NIR II) biowindows with deep penetration and high sensitivity are widely used for optical diagnosis and phototherapy. Here, a novel kind of 2D SnTe@MnO₂‐SP nanosheet (NS)‐based nanoplatform is developed for cancer theranostics with NIR II‐mediated precise optical imaging and effective photothermal ablation of mouse xenografted tumors. The 2D SnTe@MnO₂‐SP NSs are fabricated via a facile method combining ball‐milling and liquid exfoliation for synthesis of SnTe NSs, and surface coating MnO₂ shell and soybean phospholipid (SP). The ultrathin SnTe@MnO₂‐SP NSs reveal notably high photothermal conversion efficiency (38.2% in NIR I and 43.9% in NIR II). The SnTe@MnO₂‐SP NSs inherently feature tumor microenvironment (TME)‐responsive biodegradability, and the main metabolite TeO₃^2? shows great antitumor effect, coupling synergetic chemotherapy for cancer. Moreover, the SnTe@MnO₂‐SP NSs also exhibit great potential for fluorescence, photoacoustic (PA), and photothermal imaging agents in the NIR II biowindow with much higher resolution and sensitivity. This is the first report, as far as is known, with such an inorganic nanoagent setting fluorescence/PA/photothermal imaging and photothermal therapy in NIR II biowindow and TME‐responsive biodegradability rolled into one, which provide insight into the clinical potential for cancer theranostics.