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.     

A Robust ROS Generation Strategy for Enhanced Chemodynamic/Photodynamic Therapy via H2O2/O2 Self-Supply and Ca2+ Overloading

The efficacy of cancer therapy with reactive oxygen species (ROS) as the main therapeutic medium suffers from a deficiency of oxy-substrates, for example, insufficient endogenous hydrogen peroxide (H₂O₂) in chemodynamic therapy (CDT) and inherent hypoxia in photodynamic therapy (PDT). Herein, a smart polyethylene glycol (PEG)-ylated nanosystem CaO₂@ZIF-Fe/Ce6@PEG (abbreviation as CaZFCP) is constructed to achieve H₂O₂/O₂ self-supply and Ca²⁺ overloading in tumor cells simultaneously for enhanced CDT/PDT. Under the weakly acidic tumor microenvironment, the activity components inside CaZFCP, that is, CaO₂ nanoparticles, Fe²⁺, and photosensitizer Chlorin e6 (Ce6) are released by the degradation of zeolitic imidazole framework-90 (ZIF-90). Thereinto, CaO₂ nanoparticles are further decomposed to generate H₂O₂ and O₂, which alleviates both the insufficient endogenous H₂O₂ and hypoxia in tumor area, thus enhancing the efficiency of CDT and PDT by producing more hydroxyl radicals and singlet oxygen. Furthermore, Ca²⁺ overloading induced by the decomposition of CaO₂ is available for amplifying intracellular oxidative stress, resulting in mitochondrial dysfunction, which further improves the efficacy of combined CDT/PDT. In vitro and in vivo experimental results confirm excellent tumor inhibition effect, which also provides a facile paradigm in ROS-involved 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.     

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.     

Self-Amplified Competitive Coordination of MnO2-Doped CeO2 Nanozyme for Synchronously Activated Combination Therapy

Tumor-specific combination therapy has shown great promise in cancer theranostics. However, the therapeutic efficacy is usually suppressed because most of the therapeutic systems are not able to synchronously activate their different therapeutic approaches and the local concentration of tumor-associated stimulus is generally insufficient to fully activate the combination therapy process. Herein, a MnO₂-doped CeO₂ nanozyme-based nanomedicine (Ce6@CMNRs) is reported for tumor-specific synchronously activated chemodynamic/photodynamic combination therapy. The tumor-overexpressed H₂O₂ substitutes the Ce6 on Ce6@CMNRs surfaces via competitive coordination and then decomposes into •OH under acidic condition, achieving the chemodynamic therapy (CDT). Meanwhile, the substituted Ce6 triggers photodynamic therapy (PDT) under laser irradiation that is suppressed before the substitution occurs. Thus, H₂O₂ can synchronously activate both CDT and PDT of Ce6@CMNRs with a similar level in tumor sites. Moreover, the activated PDT-induced oxygen starvation further triggers the generation of H₂O₂ to continuously replace the residual Ce6 coordinated on the nanorod surface, thereby leading to the full activation of PDT and CDT. Also, the doped MnO₂ enhances the generation of •OH and provides high contrast for magnetic resonance imaging (MRI) with the help of glutathione. Therefore, Ce6@CMNRs are promising candidates for MRI-guided CDT/PDT combination therapy with minimized side effects and high efficiency.     

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.     

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.     

Phase‐Change Materials Based Nanoparticles for Controlled Hypoxia Modulation and Enhanced Phototherapy

Tumor hypoxia strengthens tumor resistance to different therapies especially oxygen involved strategies, such as photodynamic therapy (PDT). Herein, the thermal responsive phase change materials (PCM) are utilized to coencapsulate ultrasmall manganese dioxide (sMnO₂) and organic photosensitizer IR780 to obtain IR780‐sMnO₂‐PCM nanoparticles for controlled tumor hypoxia modulation and enhanced phototherapy. The thermal responsive protective PCM layer can not only prevent IR780 from photodegradation, but also immediately release sMnO₂ to decompose endogenous H₂O₂ and generate enough oxygen for PDT under laser irradiation. Owing to the efficient accumulation of IR780‐sMnO₂‐PCM nanoparticles in tumor under intravenous injection as revealed by both florescence imaging and photoacoustic imaging, the tumor hypoxia is greatly relieved. Furthermore, in vivo combined photothermal therapy (PTT) and PDT, IR780‐sMnO₂‐PCM nanoparticles, compared to IR780‐PCM nanoparticles, exhibit better performance in inhibiting tumor growth. The results highlight the promise of IR780‐sMnO₂‐PCM in controlled modulation of tumor hypoxia to overcome current limitations of cancer therapies.     

MnO2 Gatekeeper: An Intelligent and O2‐Evolving Shell for Preventing Premature Release of High Cargo Payload Core,Overcoming Tumor Hypoxia,and Acidic H2O2‐Sensitive MRI

Premature leakage of photosensitizer (PS) from nanocarriers significantly reduces the accumulation of PS within a tumor, thereby enhancing nonspecific accumulation in normal tissues, which inevitably leads to a limited efficacy for photodynamic therapy (PDT) and the enhanced systematic phototoxicity. Moreover, local hypoxia of the tumor tissue also seriously hinders the PDT. To overcome these limitations, an acidic H₂O₂‐responsive and O₂‐evolving core–shell PDT nanoplatform is developed by using MnO₂ shell as a switchable shield to prevent the premature release of loaded PS in core and elevate the O₂ concentration within tumor tissue. The inner core SiO₂‐methylene blue obtained by co‐condensation has a high PS payload and the outer MnO₂ shell shields PS from leaking into blood after intravenous injection until reaching tumor tissue. Moreover, the shell MnO₂ simultaneously endows the theranostic nanocomposite with redox activity toward H₂O₂ in the acidic microenvironment of tumor tissue to generate O₂ and thus overcomes the hypoxia of cancer cells. More importantly, the Mn(ΙΙ) ion reduced from Mn(ΙV) is capable of in vivo magnetic resonance imaging selectively in response to overexpressed acidic H₂O₂. The facile incorporation of the switchable MnO₂ shell into one multifunctional diagnostic and therapeutic nanoplatform has great potential for future clinical application.     

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.     

Fluorinated Polyethylenimine to Enable Transmucosal Delivery of Photosensitizer‐Conjugated Catalase for Photodynamic Therapy of Orthotopic Bladder Tumors Postintravesical Instillation

Photodynamic therapy (PDT) by insertion of an optical fiber into the bladder cavity has been applied in the clinic for noninvasive treatment of bladder tumors. To avoid systemic phototoxicity, bladder intravesical instillation of a photosensitizer may be an ideal approach for PDT treatment of bladder cancer, in comparison to conventional intravenous injection. However, the instillation‐based PDT for bladder cancer treatment remains to be less effective due to the poor urothelial uptake of photosensitizer, as well as the tumor hypoxia‐associated PDT resistance. Herein, it is uncovered that fluorinated polyethylenimine (F‐PEI) achieved by mixing with Chorin‐e6‐conjugated catalase (CAT‐Ce6) is able to form self‐assembled CAT‐Ce6/F‐PEI nanoparticles, which show greatly improved cross‐membrane, transmucosal, and intratumoral penetration capacities compared with CAT‐Ce6 alone or nonfluorinated CAT‐Ce6/PEI nanoparticles. Owing to the decomposition of tumor endogenous H₂O₂ by CAT‐Ce6/F‐PEI nanoparticles penetrating into bladder tumors, the tumor hypoxia would be effectively relieved to further favor PDT. Therefore, bladder intravesical instillation with CAT‐Ce6/F‐PEI nanoparticles could offer remarkably improved photodynamic therapeutic effect to destruct orthotopic bladder tumors with reduced systemic toxicity compared to hematoporphyrin, the first‐line photosensitizer used for bladder cancer PDT in clinic. This work presents a unique photosensitizer nanomedicine formulation, promising for clinical translation in instillation‐based PDT to treat bladder tumors.     

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.     

Biodegradable Calcium Phosphate Nanotheranostics with Tumor-Specific Activatable Cascade Catalytic Reactions-Augmented Photodynamic Therapy

Photodynamic therapy (PDT) is exploited as a promising strategy for cancer treatment. However, the hypoxic solid tumor and the lack of tumor-specific photosensitizer administration hinder the further application of oxygen (O₂)-dependent PDT. In this study, a biodegradable and O₂ self-supplying nanoplatform for tumor microenvironment (TME)-specific activatable cascade catalytic reactions-augmented PDT is reported. The nanoplatform (named GMCD) is constructed by coloading catalase (CAT) and sinoporphyrin sodium (DVDMS) in the manganese (Mn)-doped calcium phosphate mineralized glucose oxidase (GOx) nanoparticles. The GMCD can effectively accumulate in tumor sites to achieve an “off to on” fluorescence transduction and a TME-activatable magnetic resonance imaging. After internalization into cancer cells, the endogenous hydrogen peroxide (H₂O₂) can be catalyzed to generate O₂ by CAT, which not only promotes GOx catalytic reaction to consume more intratumoral glucose, but also alleviates tumor hypoxia and enhances the production of cytotoxic singlet oxygen from light-triggered DVDMS. Moreover, the H₂O₂ generated by GOx-catalysis can be converted into highly toxic hydroxyl radicals by Mn²⁺-mediated Fenton-like reaction, further amplifying the oxidative damage of cancer cells. As a result, GMCD displays superior therapeutic effects on 4T1-tumor bearing mice by a long term cascade catalytic reactions augmented PDT.     

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.     

Linear Chimeric Triblock Molecules Self‐Assembled Micelles with Controllably Transformable Property to Enhance Tumor Retention for Chemo‐Photodynamic Therapy of Breast Cancer

Although nanoparticles are expected to revolutionize cancer treatment, their low efficacy remains the greatest limiting factor. Recent investigations found that nanoparticles' golden principle, the enhanced permeability and retention (EPR) effect, is limited by the complicated tumor microenvironment. Herein, novel transformable nanomaterials are designed to utilize the EPR effect more effectively. By tandem conjugation of the hydrophobic head (chlorin e6 (Ce6) or bilirubin (BR)), peptide to form hydrogen bond (Phe‐Phe‐Val‐Leu‐Lys (FFVLK)), and hydrophilic tail (polyethylene glycol (PEG)), chimeric molecules that can form micelles (Ce6/BR‐FFVLK‐PEG) in aqueous solution are synthesized. Notably, the spherical micelles retain shape transformability. After circulation and distribution, they respond to 650 nm laser irradiation, and morphologically change into nanofibers so as to facilitate their retention markedly inside the tumor. Upon loading a reactive oxygen species‐responsive paclitaxel dimer with thioketal linker (PTX₂‐TK), the resultant PTX₂‐TK@Ce6/BR‐FFVLK‐PEG nanomedicine serves as a potent chemo‐photodynamic therapeutic for cancer treatment. Evaluations at both cell level and animal level reveal that PTX₂‐TK@Ce6/BR‐FFVLK‐PEG exhibits superior biocompatibility and biodistribution, and suppresses 82.6% of in vitro cell growth and 61.8% of in vivo tumor growth at a common dose of intravenous injection (10 mg kg^?1 PTX and 3.3 mg kg^?1 Ce6), becoming a novel nanomedicine with extraordinary potential in cancer therapy.     

Photostable Iodinated Silica/Porphyrin Hybrid Nanoparticles with Heavy‐Atom Effect for Wide‐Field Photodynamic/Photothermal Therapy Using Single Light Source

Physical therapies including photodynamic therapy (PDT) and photothermal therapy (PTT) can be effective against diseases that are resistant to chemotherapy and remain as incurable malignancies (for example, multiple myeloma). In this study, to enhance the treatment efficacy for multiple myeloma using the synergetic effect brought about by combining PDT and PTT, iodinated silica/porphyrin hybrid nanoparticles (ISP HNPs) with high photostability are developed. They can generate both ¹O₂ and heat with irradiation from a light‐emitting diode (LED), acting as photosensitizers for PDT/PTT combination treatment. ISP HNPs exhibit the external heavy atom effect, which significantly improves both the quantum yield for ¹O₂ generation and the light‐to‐heat conversion efficiency. The in vivo fluorescence imaging demonstrates that ISP HNPs, modified with folic acid and polyethylene glycol (FA‐PEG‐ISP HNPs), locally accumulate in the tumor after 18 h of their intravenous injection into tumor‐bearing mice. The LED irradiation on the tumor area of the mice injected with FA‐PEG‐ISP HNPs causes necrosis of the tumor tissues, resulting in the inhibition of tumor growth and an improvement in the survival rate.     

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.     

Reactive Oxygen Species–Activatable Liposomes Regulating Hypoxic Tumor Microenvironment for Synergistic Photo/Chemodynamic Therapies

Tumors have adapted various cellular antidotes and microenvironmental conditions to subsist against photodynamic therapy (PDT) and chemodynamic therapy (CDT). Here, the development of reactive oxygen species (ROS)‐activatable liposomes (RALP) for therapeutic enhancement by simultaneously addressing the critical questions in PDT and CDT is reported. The design of RALP@HOC@Fe₃O₄ features ROS‐cleavable linker molecules for improved tumor penetration/uptake and ondemand cargo releasing, and integration of Fe₃O₄ and an oxaliplatin prodrug for smart regulation of hypoxia tumor microenvironment. Glutathione stored by the tumor cells is consumed by the prodrug to produce highly toxic oxaliplatin. Depletion of glutathione not only avoids the undesired annihilation of ROS in PDT, but also modulates the chemical specie equilibria in tumors for H₂O₂ promotion, leading to greatly relieved tumor hypoxia and PDT enhancement. Synergistically, Fe (II) in the hybrid RALP formulation can be fuelled by H₂O₂ to generate ?OH in the Fenton reaction, thus elevating CDT efficiency. This work offers a strategy for harnessing smart, responsive, and biocompatible liposomes to enhance PDT and CDT by regulating tumor microenvironment, highlighting a potential clinical translation beneficial to patients with cancer.     

Black Phosphorus Quantum Dots Encapsulated Biodegradable Hollow Mesoporous MnO2: Dual-Modality Cancer Imaging and Synergistic Chemo-Phototherapy

To achieve an accurate diagnosis and efficient tumor treatment, developing a facile and powerful strategy to build multifunctional nanotheranostics is highly desirable. Benefiting from the distinct characteristics of black phosphorus quantum dots (BPQDs), herein, a versatile nanoprobe (H-MnO₂/DOX/BPQDs) is constructed for dual-modality cancer imaging and synergistic chemo-phototherapy. The hollow mesoporous MnO₂ (H-MnO₂) nanoparticles are sequentially decorated with a cationic polymer poly (allylamine hydrochloride) (PAH) and an anionic polymer poly (acrylic acid) (PAA). The obtained H-MnO₂-PAH-PAA is covalently grafted with BPQDs-PEG-NH₂ via a carbodiimide cross-linking reaction and then loaded with anti-cancer drug DOX to form final nanoprobe H-MnO₂/DOX/BPQDs. Under the tumor microenvironment, H-MnO₂/DOX/BPQDs is degraded to release encapsulated functional molecules DOX and BPQDs. DOX acts as the chemotherapy and fluorescence imaging agent, and BPQDs endows the nanoprobe with photodynamic therapy (PDT) and photothermal therapy (PTT) abilities under dual laser irradiation of 630 and 808 nm. H-MnO₂ offers contrasts for magnetic resonance imaging (MRI) and facilitates conversion of endogenous H₂O₂ to oxygen, thereby relieving tumor hypoxia and enhancing PDT efficacy. All in vitro and in vivo results demonstrate that the designed nanoprobe displays dual-modality MRI/FL imaging and synergistic chemotherapy/PDT/PTT, which ultimately enhances the accuracy of cancer diagnosis and therapeutic performance.