pH‐Sensitive Dissociable Nanoscale Coordination Polymers with Drug Loading for Synergistically Enhanced Chemoradiotherapy

Although various types of radiosensitizers based on nanoparticles are explored to enhance radiotherapy via different mechanisms, nanoscale radiosensitizers with full biodegradability, sensitive responsiveness to the tumor microenvironment, as well as the ability to greatly amplify radiation‐induced tumor destruction are still demanded. Herein, this study designs nanoscale coordination polymers (NCPs) based on acidic sensitive linker and high Z number element hafnium (Hf) ions. Chloro(triphenylphosphine)gold(I) (TPPGC), a chemotherapeutic drug, is successfully loaded into those NCPs after they are coated with polyethylene glycol (PEG). Owing to the acid‐triggered cleavage of the organic linker, such formed NCP‐PEG/TPPGC nanoparticles would be dissociated under reduced pH within the tumor, leading to the release of TPPGC to induce mitochondrial damage and arrest the cell cycle of tumor cells into the radiosensitive phase (G1). Meanwhile, Hf ions are able to act as radiosensitizers by absorbing X‐ray and depositing radiation energy within tumors. With efficient tumor accumulation after intravenous injection, NCP‐PEG/TPPGC offers remarkable synergistic therapeutic outcome in chemoradiotherapy without appreciable toxic side effect. This work thus presents a biodegradable nano‐radiosensitizer with in vivo tumor‐specific decomposition/drug release profiles and great efficacy in chemoradiotherapy of cancer.     

FeSe2‐Decorated Bi2Se3 Nanosheets Fabricated via Cation Exchange for Chelator‐Free 64Cu‐Labeling and Multimodal Image‐Guided Photothermal‐Radiation Therapy

Multifunctional theranostic agents have become rather attractive to realize image‐guided combination cancer therapy. Herein, a novel method is developed to synthesize Bi₂Se₃ nanosheets decorated with mono‐dispersed FeSe₂ nanoparticles (FeSe₂/Bi₂Se₃) for tetra‐modal image‐guided combined photothermal and radiation tumor therapy. Interestingly, upon addition of Bi(NO₃)₃, pre‐made FeSe₂ nanoparticles via cation exchange would be gradually converted into Bi₂Se₃ nanosheets, on which remaining FeSe₂ nanoparticles are decorated. The yielded FeSe₂/Bi₂Se₃ composite‐nanostructures are then modified with polyethylene glycol (PEG). Taking advantages of the high r ₂ relaxivity of FeSe₂, the X‐ray attenuation ability of Bi₂Se₃, the strong near‐infrared optical absorbance of the whole nanostructure, as well as the chelate‐free radiolabeling of ⁶⁴Cu on FeSe₂/Bi₂Se₃‐PEG, in vivo magnetic resonance/computer tomography/photoacoustic/position emission tomography multimodal imaging is carried out, revealing efficient tumor homing of FeSe₂/Bi₂Se₃‐PEG after intravenous injection. Utilizing the intrinsic physical properties of FeSe₂/Bi₂Se₃‐PEG, in vivo photothermal and radiation therapy to achieve synergistic tumor destruction is then realized, without causing obvious toxicity to the treated animals. This work presents a unique method to synthesize composite‐nanostructures with highly integrated functionalities, promising not only for nano‐biomedicine but also potentially for other different nanotechnology fields.     

Modulation of Hypoxia in Solid Tumor Microenvironment with MnO2 Nanoparticles to Enhance Photodynamic Therapy

Hypoxia not only promotes tumor metastasis but also strengthens tumor resistance to therapies that demand the involvement of oxygen, such as radiation therapy and photodynamic therapy (PDT). Herein, taking advantage of the high reactivity of manganese dioxide (MnO₂) nanoparticles toward endogenous hydrogen peroxide (H₂O₂) within the tumor microenvironment to generate O₂, multifunctional chlorine e6 (Ce6) loaded MnO₂ nanoparticles with surface polyethylene glycol (PEG) modification (Ce6@MnO₂‐PEG) are formulated to achieve enhanced tumor‐specific PDT. In vitro studies under an oxygen‐deficient atmosphere uncover that Ce6@MnO₂‐PEG nanoparticles could effectively enhance the efficacy of light‐induced PDT due to the increased intracellular O₂ level benefited from the reaction between MnO₂ and H₂O₂, the latter of which is produced by cancer cells under the hypoxic condition. Owing to the efficient tumor homing of Ce6@MnO₂‐PEG nanoparticles upon intravenous injection as revealed by T1‐weighted magnetic resonance imaging, the intratumoral hypoxia is alleviated to a great extent. Thus, in vivo PDT with Ce6@MnO₂‐PEG nanoparticles even at a largely reduced dose offers remarkably improved therapeutic efficacy in inhibiting tumor growth compared to free Ce6. The results highlight the promise of modulating unfavorable tumor microenvironment with nanotechnology to overcome current limitations of cancer therapies.     

Imaging‐Guided pH‐Sensitive Photodynamic Therapy Using Charge Reversible Upconversion Nanoparticles under Near‐Infrared Light

Photodynamic therapy (PDT) based on upconversion nanoparticles (UCNPs) can effectively destroy cancer cells under tissue‐penetrating near‐infrared light (NIR) light. Herein, we synthesize manganese (Mn²⁺)‐doped UCNPs with strong red light emission at ca. 660 nm under 980 nm NIR excitation to activate Chlorin e6 (Ce6), producing singlet oxygen (¹O₂) to kill cancer cells. A layer‐by‐layer (LbL) self‐assembly strategy is employed to load multiple layers of Ce6 conjugated polymers onto UCNPs via electrostatic interactions. UCNPs with two layers of Ce6 loading (UCNP@2xCe6) are found to be optimal in terms of Ce6 loading and ¹O₂ generation. By further coating UCNP@2xCe6 with an outer layer of charge‐reversible polymer containing dimethylmaleic acid (DMMA) groups and polyethylene glycol (PEG) chains, we obtain a UCNP@2xCe6‐DMMA‐PEG nanocomplex, the surface of which is negatively charged and PEG coated under pH 7.4; this could be converted to have a positively charged naked surface at pH 6.8, significantly enhancing cell internalization of nanoparticles and increasing in vitro NIR‐induced PDT efficacy. We then utilize the intrinsic optical and paramagnetic properties of Mn²⁺‐doped UCNPs for in vivo dual modal imaging, and uncover an enhanced retention of UCNP@2xCe6‐DMMA‐PEG inside the tumor after intratumoral injection, owing to the slightly acidic tumor microenvironment. Consequently, a significantly improved in vivo PDT therapeutic effect is achieved using our charge‐reversible UCNP@2xCe6‐DMMA‐PEG nanoparticles. Finally, we further demonstrate the remarkably enhanced tumor‐homing of these pH‐responsive charge‐switchable nanoparticles in comparison to a control counterpart without pH sensitivity after systemic intravenous injection. Our results suggest that UCNPs with finely designed surface coatings could serve as smart pH‐responsive PDT agents promising in cancer theranostics.     

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.     

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.     

An O2 Self‐Supplementing and Reactive‐Oxygen‐Species‐Circulating Amplified Nanoplatform via H2O/H2O2 Splitting for Tumor Imaging and Photodynamic Therapy

Conventional photodynamic therapy (PDT) has limited applications in clinical cancer therapy due to the insufficient O₂ supply, inefficient reactive oxygen species (ROS) generation, and low penetration depth of light. In this work, a multifunctional nanoplatform, upconversion nanoparticles (UCNPs)@TiO₂@MnO₂ core/shell/sheet nanocomposites (UTMs), is designed and constructed to overcome these drawbacks by generating O₂ in situ, amplifying the content of singlet oxygen (¹O₂) and hydroxyl radical (?OH) via water‐splitting, and utilizing 980 nm near‐infrared (NIR) light to increase penetration depth. Once UTMs are accumulated at tumor site, intracellular H₂O₂ is catalyzed by MnO₂ nanosheets to generate O₂ for improving oxygen‐dependent PDT. Simultaneously, with the decomposition of MnO₂ nanosheets and 980 nm NIR irradiation, UCNPs can efficiently convert NIR to ultraviolet light to activate TiO₂ and generate toxic ROS for deep tumor therapy. In addition, UCNPs and decomposed Mn²⁺ can be used for further upconversion luminescence and magnetic resonance imaging in tumor site. Both in vitro and in vivo experiments demonstrate that this nanoplatform can significantly improve PDT efficiency with tumor imaging capability, which will find great potential in the fight against tumor.     

Nanostructured Alkaline‐Cation‐Containing δ‐MnO2 for Photocatalytic Water Oxidation

Oxygen evolution from water is one of the key reactions for solar fuel production. Here, two nanostructured K‐containing δ‐MnO₂ are synthesized: K‐δ‐MnO₂ nanosheets and K‐δ‐MnO₂ nanoparticles, both of which exhibit high catalytic activity in visible‐light‐driven water oxidation. The role of alkaline cations in oxygen evolution is first explored by replacing the K⁺ ions in the δ‐MnO₂ structure with H⁺ ions through proton ion exchange. H‐δ‐MnO₂ catalysts with a similar morphology and crystal structure exhibit activities per surface site approximately one order of magnitude lower than that of K‐δ‐MnO₂, although both nanostructured H‐δ‐MnO₂ catalysts have much larger Brunauer–Emmett–Teller (BET) surface areas. Such a low turnover frequency (TOF) per surface Mn atom might be due to the fact that the Ru²⁺(bpy)₃ sensitizer is too large to access the additional surface area created during proton exchange. Also, a prepared Na‐containing δ‐MnO₂ material with an identical crystal structure exhibits a TOF similar to that of the K‐containing δ‐MnO₂, suggesting that the alkaline cations are not directly involved in catalytic water oxidation, but instead stabilize the layered structure of the δ‐MnO₂.     

Bottom‐Up Preparation of Uniform Ultrathin Rhenium Disulfide Nanosheets for Image‐Guided Photothermal Radiotherapy

Facile preparation of multifunctional theranostic nanoplatforms with well‐controlled morphology and sizes remains an attractive in the area of nanomedicine. Here, a new kind of 2D transition metal dichalcogenide, rhenium disulfide (ReS₂) nanosheets, with uniform sizes, strong near‐infrared (NIR) light, and strong X‐ray attenuation, is successfully synthesized. After surface modification with poly(ethylene glycol) (PEG), the synthesized ReS₂‐PEG nanosheets are stable in various physiological solutions. In addition to their contrasts in photoacoustic imaging and X‐ray computed tomography imaging because of their strong NIR light and X‐ray absorptions, respectively, such ReS₂‐PEG nanosheets can also be tracked under nuclear imaging after chelator‐free labeling with radioisotope ions, ^99mTc⁴⁺. Efficient tumor accumulation of ReS₂‐PEG nanosheets is then observed after intravenous injection into tumor‐bearing mice under triple‐modal imaging. The combined in vivo photothermal radiotherapy is further conducted, achieving a remarkable synergistic tumor destruction effect. Finally, no obvious toxicity of ReS₂‐PEG nanosheets is observed from the treated mice within 30 d. This work suggests that such ultrathin ReS₂ nanosheets with well‐controlled morphology and uniform sizes may be a promising type of multifunctional theranostic agent for remotely triggered cancer combination therapy.     

Remarkable NIR Enhancement of Multifunctional Nanoprobes for In Vivo Trimodal Bioimaging and Upconversion Optical/T2‐Weighted MRI‐Guided Small Tumor Diagnosis

Effective nanoprobes and contrast agents are urgently sought for early‐stage cancer diagnosis. Upconversion nanoparticles (UCNPs) are considerable alternatives for bioimaging, cancer diagnosis, and therapy. Yb³⁺/Tm³⁺ co‐doping brings both emission and excitation wavelengths into the near‐infrared (NIR) region, which is known as “optical transmission window” and ideally suitable for bioimaging. Here, NIR emission intensity is remarkably enhanced by 113 times with the increase of Yb³⁺ concentration from 20% to 98% in polyethylene glycol (PEG) modified NaYF₄:Yb³⁺/Tm³⁺ UCNPs. PEG‐UCNPs‐5 (98% Yb³⁺) can act as excellent nanoprobes and contrast agents for trimodal upconversion (UC) optical/CT/T₂‐weighted magnetic resonance imaging (MRI). In addition, the enhanced detection of lung in vivo long‐lasting tracking, as well as possible clearance mechanism and excretion routes of PEG‐UCNPs‐5 have been demonstrated. More significantly, a small tumor down to 4 mm is detected in vivo via intravenous injection of these nanoprobes under both UC optical and T₂‐weighted MRI modalities. PEG‐UCNPs‐5 can emerge as bioprobes for multi‐modal bioimaging, disease diagnosis, and therapy, especially the early‐stage tumor diagnosis.     

Metal–Organic Framework (MOF) Derived Electrodes with Robust and Fast Lithium Storage for Li‐Ion Hybrid Capacitors

Hybrid metal–organic frameworks (MOFs) demonstrate great promise as ideal electrode materials for energy‐related applications. Herein, a well‐organized interleaved composite of graphene‐like nanosheets embedded with MnO₂ nanoparticles (MnO₂@C‐NS) using a manganese‐based MOF and employed as a promising anode material for Li‐ion hybrid capacitor (LIHC) is engineered. This unique hybrid architecture shows intriguing electrochemical properties including high reversible specific capacity 1054 mAh g^?1 (close to the theoretical capacity of MnO₂, 1232 mAh g^?1) at 0.1 A g^?1 with remarkable rate capability and cyclic stability (90% over 1000 cycles). Such a remarkable performance may be assigned to the hierarchical porous ultrathin carbon nanosheets and tightly attached MnO₂ nanoparticles, which provide structural stability and low contact resistance during repetitive lithiation/delithiation processes. Moreover, a novel LIHC is assembled using a MnO₂@C‐NS anode and MOF derived ultrathin nanoporous carbon nanosheets (derived from other potassium‐based MOFs) cathode materials. The LIHC full‐cell delivers an ultrahigh specific energy of 166 Wh kg^?1 at 550 W kg^?1 and maintained to 49.2 Wh kg^?1 even at high specific power of 3.5 kW kg^?1 as well as long cycling stability (91% over 5000 cycles). This work opens new opportunities for designing advanced MOF derived electrodes for next‐generation energy storage devices.     

Non‐Fenton‐Type Hydroxyl Radical Generation and Photothermal Effect by Mitochondria‐Targeted WSSe/MnO2 Nanocomposite Loaded with Isoniazid for Synergistic Anticancer Treatment

Here, in terms of the highly reactive oxidative hydroxyl radical (?OH) generation ability of isoniazid (INH) catalyzed by Mn²⁺ ion and the photothermal effect of WSSe nanoflakes, a WSSe/MnO₂‐INH nanocomposite for synergistic anticancer treatment is developed. Advanced INH‐induced ?OH formation ability is systemically demonstrated in the presence of manganese and relevant non‐Fenton‐type mechanism, and good photothermal conversion efficiency of the WSSe/MnO₂ nanocomposite. After modifying with mitochondria‐targeted triphenylphosphonium bromide (TPP) moieties and camouflaging with cancer cells membrane (WSSe/MnO₂‐INH‐TPP@CM), it confers a sequential cell‐to‐mitochondria targeting ability. In vivo X‐ray computed tomography and magnetic resonance tumor imaging capability of the nanocomposite are also revealed. The mitochondria‐targeted oxidative damage and photothermal therapy by WSSe/MnO₂‐INH‐TPP@CM results in excellent anticancer treatment efficacy both in vitro and in vivo. This is the first exploration of the possibility of non‐Fenton‐type ?OH formation for anticancer treatment, which opens new opportunities for ROS‐based and combined cancer treatment strategies.     

Manganese‐Based Functional Nanoplatforms: Nanosynthetic Construction,Physiochemical Property,and Theranostic Applicability

Transition metal‐based nanoparticles have shown their broad applications in versatile biomedical applications. Although traditional iron‐based nanoparticles have been extensively explored in biomedicine, transition metal manganese (Mn)‐based nanoparticulate systems have emerged as a multifunctional nanoplatform with their intrinsic physiochemical property and biological effect for satisfying the strict biomedical requirements. This comprehensive review focuses on recent progress of Mn‐based functional nanoplatforms in biomedicine with the particular discussion on their elaborate construction, physiochemical property, and theranostic applicability. Several Mn‐based nanosystems are discussed in detail, including solid/hollow MnO_x nanoparticles, 2D MnO_x nanosheets, MnO_x‐silica/mesoporous silica nanoparticles, MnO_x‐Fe₃O₄ nanoparticles, MnO_x‐Au, MnO_x‐fluorescent nanoparticles, Mn‐based organic composite nanosystem, and some specific/unique Mn‐based nanocomposites. Their versatile biomedical applications include pH/reducing‐responsive T₁‐weighted positive magnetic resonance imaging, controlled drug loading/delivery/release, protection of neurological disorder, photothermal hyperthermia, photodynamic therapy, chemodynamic therapy, alleviation of tumor hypoxia, immunotherapy, and some specific synergistic therapies, which are based on their disintegration behavior under the mildly acidic/reducing condition, multiple enzyme‐mimicking activity, catalytic‐triggering Fenton reaction, etc. The biological effects and biocompatibility of these Mn‐based nanosystems are also discussed, accompanied with a discussion on challenges/critical issues and an outlook on the future developments and clinical‐translation potentials of these intriguing Mn‐based functional nanoplatforms.     

Renal‐Clearable PEGylated Porphyrin Nanoparticles for Image‐Guided Photodynamic Cancer Therapy

Nanomaterials with renal clearance from the body within a reasonable timescale have shown great promises in the area of nanomedicine recently. However, the integration of theranostic and renal clearance properties into a single ultrasmall nanostructure remains a great challenge. Herein, meso‐tetra(4‐carboxyphenyl)porphyrin (TCPP) structure is utilized as a model, for the first time using noninvasive dynamic positron emission tomography (PET) imaging to investigate the balance of the renal clearance and tumor uptake behaviors of polyethylene glycol (PEG)‐modified porphyrin nanoparticles (TCPP‐PEG) with various molecular weights. This study finds that TCPP‐PEG nanoparticles with larger molecular weight show higher tumor uptake due to the enhanced permeability and retention effect, while the lower ones tend to be better for renal clearance. Based on dynamic PET and fluorescence dual‐modal imaging modalities, the TCPP‐PEG_10K nanoparticles seem to be an excellent choice for the balance of renal clearance and tumor retention. In vitro and in vivo photodynamic therapy confirms an excellent therapeutic efficacy. Therefore, this work presents a simplified approach to fabricate and select biocompatible multifunctional TCPP‐PEG‐based theranostic agents with renal clearance behavior, which highlights the clinical application potential of TCPP‐PEG nanoparticles as theranostic probes for imaging‐guided cancer therapy.     

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.     

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.     

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.     

Photoacoustic Imaging Guided Near‐Infrared Photothermal Therapy Using Highly Water‐Dispersible Single‐Walled Carbon Nanohorns as Theranostic Agents

The poly(maleic anhydride‐alt‐1‐octadecene‐poly(ethylene glycol)) (C₁₈PMH‐PEG) modified single‐walled carbon nanohorns (SWNHs) are designed with high stability and biocompatibility. The as‐prepared SWNHs/C₁₈PMH‐PEG not only can serve as an excellent photothermal agent but also can be used as a promising photoacoustic imaging (PAI) agent both in vitro and in vivo due to its strong absorption in the near infrared (NIR) region. The PAI result reveals that the SWNHs/C₁₈PMH‐PEG possesses ultra long blood circulation time and can significantly be accumulated at the tumor site through the enhanced penetration and retention (EPR) effect. The maximum accumulation of SWNHs/C₁₈PMH‐PEG at tumor site could be achieved at the time point of 24 h after intravenous injection, which is considered to be the optimal time for the 808 nm laser treatment. The subsequent photothermal ablation of tumors can be achieved without triggering any side effects. Therefore, a PAI guided PTT platform based on SWNHs is proposed and highlights the potential theranostic application for biomedical uses.     

Biocompatible,Uniform, and Redispersible Mesoporous Silica Nanoparticles for Cancer‐Targeted Drug Delivery In Vivo

Engineering multifunctional nanocarriers for targeted drug delivery shows promising potentials to revolutionize the cancer chemotherapy. Simple methods to optimize physicochemical characteristics and surface composition of the drug nanocarriers need to be developed in order to tackle major challenges for smooth translation of suitable nanocarriers to clinical applications. Here, rational development and utilization of multifunctional mesoporous silica nanoparticles (MSNPs) for targeting MDA‐MB‐231 xenograft model breast cancer in vivo are reported. Uniform and redispersible poly(ethylene glycol)‐incorporated MSNPs with three different sizes (48, 72, 100 nm) are synthesized. They are then functionalized with amino‐β‐cyclodextrin bridged by cleavable disulfide bonds, where amino‐β‐cyclodextrin blocks drugs inside the mesopores. The incorporation of active folate targeting ligand onto 48 nm of multifunctional MSNPs (PEG‐MSNPs48‐CD‐PEG‐FA) leads to improved and selective uptake of the nanoparticles into tumor. Targeted drug delivery capability of PEG‐MSNPs48‐CD‐PEG‐FA is demonstrated by significant inhibition of the tumor growth in mice treated with doxorubicin‐loaded nanoparticles, where doxorubicin is released triggered by intracellular acidic pH and glutathione. Doxorubicin‐loaded PEG‐MSNPs48‐CD‐PEG‐FA exhibits better in vivo therapeutic efficacy as compared with free doxorubicin and non‐targeted nanoparticles. Current study presents successful utilization of multifunctional MSNP‐based drug nanocarriers for targeted cancer therapy in vivo.     

A Novel Theranostic Nanoplatform Based on Pd@Pt‐PEG‐Ce6 for Enhanced Photodynamic Therapy by Modulating Tumor Hypoxia Microenvironment

Photodynamic therapy (PDT), which utilizes reactive oxygen species to kill cancer cells, has found wide applications in cancer treatment. However, the hypoxic nature of most solid tumors can severely restrict the efficiency of PDT. Meanwhile, the hydrophobicity and limited tumor selectivity of some photosensitizers also reduce their PDT efficacy. Herein, a photosensitizer‐Pd@Pt nanosystem (Pd@Pt‐PEG‐Ce6) is designed for highly efficient PDT by overcoming these limitations. In the nanofabrication, Pd@Pt nanoplates, exhibiting catalase‐like activity to decompose H₂O₂ to generate oxygen, are first modified with bifunctional PEG (SH‐PEG‐NH₂). Then the Pd@Pt‐PEG is further covalently conjugated with the photosensitizer chlorin e6 (Ce6) to get Pd@Pt‐PEG‐Ce6 nanocomposite. The Pd@Pt‐PEG‐Ce6 exhibits good biocompatibility, long blood circulation half‐life, efficient tumor accumulation, and outstanding imaging properties. Both in vitro and in vivo experimental results clearly indicate that Pd@Pt‐PEG‐Ce6 effectively delivers photosensitizers to cancer cells/tumor sites and triggers the decomposition of endogenous H₂O₂ to produce oxygen, resulting in a remarkably enhanced PDT efficacy. Moreover, the moderate photothermal effect of Pd@Pt nanoplates also strengthen the PDT of Pd@Pt‐PEG‐Ce6. Therefore, by integrating the merits of high tumor‐specific accumulation, hypoxia modulation function, and mild photothermal effect into a single nanoagent, Pd@Pt‐PEG‐Ce6 readily acts as an ideal nanotherapeutic platform for enhanced cancer PDT.