Surface chemistry engineered selenium nanoparticles as bactericidal and immuno-modulating dual-functional agents for combating methicillin-resistant Staphylococcus aureus Infection.

Because of the extremely complexed microenvironment of drug-resistant bacterial infection, nanomaterials with both bactericidal and immuno-modulating activities are undoubtedly the ideal modality for overcoming drug resistance. Herein, we precisely engineered the surface chemistry of selenium nanoparticles (SeNPs) using neutral (polyvinylpyrrolidone-PVP), anionic (letinan-LET) and cationic (chitosan-CS) surfactants. It was found that surface chemistry greatly influenced the bioactivities of functionalized SeNPs, their interactions with methicillin-resistant Staphylococcus aureus (MRSA), immune cells and metabolisms. LET-functionalized SeNPs with distinct metabolisms exhibited the best inhibitory efficacy compared to other kinds of SeNPs against MRSA through inducing robust ROS generation and damaging bacterial cell wall. Meanwhile, only LET-SeNPs could effectively activate natural kill (NK) cells, and enhance the phagocytic capability of macrophages and its killing activity against bacteria. Furthermore, in vivo studies suggested that LET-SeNPs treatment highly effectively combated MRSA infection and promoted wound healing by triggering much more mouse NK cells, CD8+ and CD4+ T lymphocytes infiltrating into the infected area at the early stage to efficiently eliminate MRSA in the mouse model. This study demonstrates that the novel functionalized SeNP with dual functions could serve as an effective antibacterial agent and could guide the development of next generation antibacterial agents.

Universal Fe/Mn Nanoadjuvant with T1/T2 MRI Self-Navigation and Gas Generation for Ideal Vaccines with Precise Tracking.

Because of the distinguished properties between nanovaccine and traditional vaccine, the precise guidelines for nanovaccines with an optimal vaccination strategy to induce ideal immunities are greatly desired for combating major diseases, including cancer and infections. Herein, we designed and synthesized a self-navigating nanoadjuvant composed of Fe-doped manganese carbonate and its nanovaccine via a facile method. First, the degradation of the nanoadjuvant under acidic milieu of immune cells in lymph nodes would generate T1 and T2 MR imaging (MRI) signals to reflect the transformation dynamics of the nanovaccine and inform us when the next vaccination needed. Under this guideline, nanovaccines with a precise vaccination strategy triggered robust antigen-specific immune responses and immunological memory to effectively prevent ovalbumin (OVA)-expressing melanoma relapse by activating dendritic cells via a stimulator of interferon genes (STING) signaling pathway and inducing antigen cross-presentation by shaping lysosome integrity with CO2 generation and upregulating transporter associated antigen processing 1 (TAP-1) transporter. This study provides a universal nanoadjuvant with imaging self-guidance, immunopotentiating, and cross-priming activities for developing precise vaccines with an optimal immunization strategy to combat major diseases.

Designing Selenium Nanoadjuvant as Universal Agent for Live-Killed Virus-Based Vaccine.

Inactivated virus vaccines with whole antigen spectra and good safety are the commonly used modality for preventing infections. However, the poor immunogenicity greatly limits its clinical applications. Herein, by taking advantages of the crucial roles of Se in the functions of immune cells and its biomineralization property, it successfully in-situ synthesized Se nanoadjuvant on inactivated viruses such as porcine epidemic diarrhea virus (PEDV), pseudorabies virus (PRV), and porcine reproductive and respiratory syndrome virus (PRRSV) in a facile method, which is universal to construct other inactivated virus vaccines. The nanovaccine can highly effectively enhance the uptake of PEDV/PRV/PRRSV into dendritic cells (DCs) and activate DCs via triggering TLR4 signaling pathways and regulating selenoproteins expressions. Furthermore, it exhibited better activities in triggering macrophages and natural killer cells-mediated innate immunity and T cells-mediated cellular immunity compared to PEDV and the commercial inactivated PEDV vaccine on both mice and swine models. This study provides a universal Se nanoadjuvant for developing inactivated viruses-based nanovaccines for preventing virus infections.

Precise Engineering of a Se/Te Nanochaperone for Reinvigorating Cancer Radio-Immunotherapy.

Facilely synthesized nanoradiosensitizers with well-controlled structure and multifunctionality are greatly desired to address the challenges of cancer radiotherapy. In this work, a universal method is developed for synthesizing chalcogen-based TeSe nano-heterojunctions (NHJs) with rod-, spindle-, or dumbbell-like morphologies by engineering the surfactant and added selenite. Interestingly, dumbbell-shaped TeSe NHJs (TeSe NDs) as chaperone exhibit better radio-sensitizing activities than the other two nanostructural shapes. Meanwhile, TeSe NDs can serve as cytotoxic chemodrugs that degrade to highly toxic metabolites in acidic environment and deplete GSH within tumor to facilitate radiotherapy. More importantly, the combination of TeSe NDs with radiotherapy significantly decreases regulatory T cells and M2-phenotype tumor-associated macrophage infiltrations within tumors to reshape the immunosuppressive microenvironment and induce robust T lymphocytes-mediated antitumor immunity, resulting in great abscopal effects on combating distant tumor progression. This study provides a universal method for preparing NHJ with well-controlled structure and developing nanoradiosensitizers to overcome the clinical challenges of cancer radiotherapy.

Selenadiazole derivative-loaded metal azolate frameworks facilitate NK cell immunotherapy by sensitizing tumor cells and shaping immuno-suppressive microenvironments.

The low sensitivity of tumor cells and immunosuppressive microenvironments lead to unsatisfactory efficacy of natural killer (NK) cell immunotherapy. In this work, we developed a safe and effective combination treatment strategy by integrating a selenadiazole derivative (PSeD)-loaded metal azolate framework (PSeD@MAF-4(R)) with NK cells derived from cancer patients against a xenograft human breast tumor model. Intriguingly, it was found that only PSeD@MAF-4(R) pretreatment on tumor cells exhibited synergistic effects with NK cells in inhibiting tumor cell growth by up-regulating NKG2D and its ligands to maximize the interactions between NK and MCF-7 cells. Moreover, PSeD@MAF-4(R) pretreatment could significantly enhance the degranulation of NK cells and regulate their secretions of pro- or anti-inflammatory cytokines (e.g. IL-6, IL-10, and TGF-ß). Furthermore, PSeD@MAF-4(R) could significantly enhance the penetration capability of NK cells into tumor spheroids. The combination treatment mainly induced G1 phase arrest and activated multiple caspase-mediated apoptosis of tumor cells. In vivo evidence showed that PSeD@MAF-4(R) combined with NK cells could highly efficiently combat breast tumor progression via inducing and activating innate immune cell (DC and NK cell) infiltrations within tumor tissues while shaping the suppressive tumor microenvironment by down-regulating the expression of TGF-ß. This developed strategy may provide important information for developing NK cell-based combination cancer immunotherapy with high efficacy and good safety profiles.

Metabolic Reprogramming of NK Cells by Black Phosphorus Quantum Dots Potentiates Cancer Immunotherapy.

Low persistence, metabolic dysfunction in microenvironment, and tumor-derived immunosuppression of Natural killer (NK) cells in patients are greatly limited the successful clinical application of NK cell-based cancer immunotherapy. Interestingly, herein that human serum albumin-encapsulated black phosphorus quantum dots (BPQDs@HSA) can effectively augment antitumor efficacy of clinical patients-derived NK cell immunotherapy is found. As the donor of phosphate group, BPQDs@HSA binds with the protein of phosphatidylinositol 4-phosphate 5-kinase type-1 gamma (PIP5K1A) and activates the downstream PI3K-Akt and mTOR signaling pathways to reprogram cell metabolism of glycolysis and further promote the oxidative phosphorylation, sequentially maintains the cell viability and immunity of NK cells. And multiomics analysis is therefore conducted to reveal the underlying immunoregulation mechanisms, and that BPQDs@HSA can interact with the Toll-like receptor (TLR) on the NK cell surface and increase the expression level of mTOR, and thus activate downstream NF-κB signalling pathways to regulate cytokine secretion and enhance immune tumoricidal is found. BPQDs@HSA can also enhance immune surveillance, relieve immune suppression, and inhibit tumor immune escape. Collectively, this study not only demonstrates a successful strategy for nanomedicine-potentiated immune-cancer therapy, but also sheds light on the understanding of interface between nanomedicine and immune cells activation.

Ruthenium complexes boost NK cell immunotherapy via sensitizing triple-negative breast cancer and shaping immuno-microenvironment.

Discovery of effective chemical sensitizers to synergize with natural killer cells immunotherapy is urgently desired to overcome its unsatisfactory efficacy in clinic. Herein, we design a series of ruthenium (Ru) polypyridyl complex to systematically explore their potentials in facilitating NK cells treatment. Intriguingly, the chemical structure greatly determines the activity of Ru complexes, while only RuPOP effectively regulates the immuno-suppressors and target proteins within tumor cells. This unique property contributes to its good capability in enhancing the sensitivity of MDA-MB-231 cells to NK cells from cancer patients. Furthermore, besides directly damaging tumor cells, RuPOP pretreatment together with NK cells can also induce robust ROS generation, activate multiple apoptosis-related receptors like TNF-R1, DR5, Fas and maximize the interactions between NK and tumor cells via up-regulating NKG2D and its multiple ligands to trigger caspase 3-dependent apoptosis. Moreover, the combination treatment exhibits high in vivo therapeutic efficacy against breast tumor through boosting the infiltration of NK cells and reducing the protumoral capability of myeloid-derived suppressor cells (MDSC). This study sheds lights for designing metal complexes to potentiate NK cells immunotherapy with clear action mechanisms and provides important information for developing more effective adoptive cell transfer therapy in clinic.

Immunosuppressive Nanoparticles for Management of Immune-Related Adverse Events in Liver.

Immune checkpoint blockade (ICB) therapy has been considered as an effective way to boost immune cells to recognize and attack tumors. However, side effects known as immune-related adverse events (irAEs) should be carefully managed. Here, we engineer immunosuppressive nanoparticles by coating PD-L1 overexpressed mesenchymal stem cells (MSCs) plasma membrane on poly lactic-co-glycolic acid nanoparticles (MSC-PD-L1+ NPs) for managing and reducing irAEs induced by immune checkpoint inhibitors. The nanoparticles can enrich at liver site after intravenous administration. In the high dose of anti-PD-L1 mAb-induced irAEs clinically relevant mouse model, a low dose of MSC-PD-L1+ NPs (2 mg/kg) sufficiently rescues hepatitis by inactivating T cells and macrophages in the liver tissue. More intriguingly, due to the dose threshold for nanoparticles to the tumor site, we unexpectedly find that the injected NPs do not affect the efficiency of ICB therapy to inhibit solid tumor growth. Such a strategy shows potential for managing the various cancer immunotherapy associated irAEs in clinical applications.

A general strategy towards personalized nanovaccines based on fluoropolymers for post-surgical cancer immunotherapy.

Cancer metastases and recurrence after surgical resection remain an important cause of treatment failure. Here we demonstrate a general strategy to fabricate personalized nanovaccines based on a cationic fluoropolymer for post-surgical cancer immunotherapy. Nanoparticles formed by mixing the fluoropolymer with a model antigen ovalbumin, induce dendritic cell maturation via the Toll-like receptor 4 (TLR4)-mediated signalling pathway, and promote antigen transportation into the cytosol of dendritic cells, which leads to an effective antigen cross-presentation. Such a nanovaccine inhibits established ovalbumin-expressing B16-OVA melanoma. More importantly, a mix of the fluoropolymer with cell membranes from resected autologous primary tumours synergizes with checkpoint blockade therapy to inhibit post-surgical tumour recurrence and metastases in two subcutaneous tumour models and an orthotopic breast cancer tumour. Furthermore, in the orthotopic tumour model, we observed a strong immune memory against tumour rechallenge. Our work offers a simple and general strategy for the preparation of personalized cancer vaccines to prevent post-operative cancer recurrence and metastasis.

Designing immunogenic nanotherapeutics for photothermal-triggered immunotherapy involving reprogramming immunosuppression and activating systemic antitumor responses.

Low tumor mutational burden and absence of T cells within the tumor sites are typical characteristics of "cold immune tumors" that paralyzes the immune system. The strategy of reversing "cold tumors" to "hot tumors" infiltrated high degree of T cells in order to activate anti-tumor immunity has attracted lots of attentions. Herein, immunogenic core-shell Au@Se NPs is fabricated by gold-selenium coordination bond to realize nanoparticles-mediated local photothermal-triggered immunotherapy. As expected, incorporation of gold nanostars (AuNSs) with improved photothermal stability and conversion efficiency promotes the disintegration and transformation of selenium nanoparticles (SeNPs), thus leading to enhanced cancer cells apoptosis by producing higher hyperthermia. Moreover, the results of in vivo experiments demonstrate that the synergy between SeNPs-mediated chemotherapy and AuNSs-induced photothermal therapy not only generated a localized antitumor-immune response with excellent cancer killing effect under the presence of tumor-associated antigens, but also effectively reprogrammed the tumor associated macrophages (TAMs) from M2 to M1 phenotype with tumoricidal activity to devour distant tumors. Without a doubt, this study not only provides a potent strategy to reverse the immunosuppressive tumor microenvironment, but also offers a new insight for potential clinical application in tumor immunotherapy.

Cell-Penetrating Peptide Enhanced Antigen Presentation for Cancer Immunotherapy.

The development of effective cancer vaccines is an important direction in the area of cancer immunotherapy. Although certain types of preventive cancer vaccines have already been used in the clinic, therapeutic cancer vaccines for treatment of already established tumors are still in high demand. In this study, we develop a new type of cancer vaccine by mixing cell-penetrating peptide (CPP) conjugated antigen as the enhanced antigen, together with CpG as the immune adjuvant. A special CPP, cytosol-localizing internalization peptide 6 (CLIP6), which has the ability to enter cells exclusively via a nonendosomal mechanism, i.e., direct translocation across the cell membrane, is conjugated with model antigen ovalbumin (OVA). Compared to naked OVA, the obtained CLIP6-OVA conjugates show greatly increased uptake by dendritic cells (DCs) and, more importantly, remarkably enhanced antigen cross-presentation, eliciting stronger cytotoxic T lymphocyte (CTL) mediated immune responses with the help of CpG. This CLIP6-OVA/CpG formulation offers effective protection for mice against challenged B16-OVA tumors, and is able to further function as a therapeutic vaccine, which, in combination with immune checkpoint blockade therapy, can significantly suppress the already-established tumors. Such a CLIP6-based cancer vaccine developing strategy shows promising potential toward clinical practice owing to its features of easy preparation, low cost, and remarkable biocompatibility.

Relaxin gene delivery mitigates liver metastasis and synergizes with check point therapy.

Activated hepatic stellate cell (aHSC)-mediated liver fibrosis is essential to the development of liver metastasis. Here, we discover intra-hepatic scale-up of relaxin (RLN, an anti-fibrotic peptide) in response to fibrosis along with the upregulation of its primary receptor (RXFP1) on aHSCs. The elevated expression of RLN serves as a natural regulator to deactivate aHSCs and resolve liver fibrosis. Therefore, we hypothesize this endogenous liver fibrosis repair mechanism can be leveraged for liver metastasis treatment via enforced RLN expression. To validate the therapeutic potential, we utilize aminoethyl anisamide-conjugated lipid-calcium-phosphate nanoparticles to deliver plasmid DNA encoding RLN. The nanoparticles preferentially target metastatic tumor cells and aHSCs within the metastatic lesion and convert them as an in situ RLN depot. Expressed RLN reverses the stromal microenvironment, which makes it unfavorable for established liver metastasis to grow. In colorectal, pancreatic, and breast cancer liver metastasis models, we confirm the RLN gene therapy results in significant inhibition of metastatic progression and prolongs survival. In addition, enforced RLN expression reactivates intra-metastasis immune milieu. The combination of the RLN gene therapy with PD-L1 blockade immunotherapy further produces a synergistic anti-metastatic efficacy. Collectively, the targeted RLN gene therapy represents a highly efficient, safe, and versatile anti-metastatic modality, and is promising for clinical translation.

Nanovaccine based on a protein-delivering dendrimer for effective antigen cross-presentation and cancer immunotherapy.

Cancer vaccines for prevention and treatment of tumors have attracted tremendous interests as a type of cancer immunotherapy strategy. A major challenge in achieving robust T-cell responses to destruct tumor cells after vaccination is the abilities of antigen cross-presentation for antigen-presenting cells (APCs) such as dendritic cells (DCs). Herein, we demonstrate that a polyamidoamine dendrimer modified with guanidinobenzoic acid (DGBA) could serve as an effective protein carrier to enable delivery of protein antigen, thereby leading to effective antigen cross-presentation by DCs. With ovalbumin (OVA) as the model antigen and unmethylated cytosine-guanine dinucleotides (CpG) as the adjuvant, a unique type of tumor vaccine is formulated. Importantly, such DGBA-OVA-CpG nanovaccine can induce robust antigen-specific cellular immunities and further demonstrates outstanding prophylactic efficacy against B16-OVA melanoma. More significantly, the nanovaccine shows excellent therapeutic effect to treat established B16-OVA melanoma when used in combination with the programmed cell death protein 1 (PD-1) checkpoint-blockade immunotherapy. This study presents the great promises of employing rationally engineered cytosolic protein carriers for the development of tumor vaccines to achieve effective cancer immunotherapy.

Light-Triggered In Situ Gelation to Enable Robust Photodynamic-Immunotherapy by Repeated Stimulations.

Photodynamic therapy (PDT) has shown the potential of triggering systemic antitumor immune responses. However, while the oxygen-deficient hypoxic tumor microenvironment is a factor that limits the PDT efficacy, the immune responses after conventional PDT usually are not strong enough to eliminate metastatic tumors. Herein, a light-triggered in situ gelation system containing photosensitizer-modified catalase together with poly(ethylene glycol) double acrylate (PEGDA) as the polymeric matrix is designed. Immune adjuvant nanoparticles are further introduced into this system to trigger robust antitumor immune responses after PDT. Following local injection of the mixed precursor solution into tumors and the subsequent light exposure, polymerization of PEGDA can be initiated to induce in situ gelation. Such hybrid hydrogel with long-term tumor retention of various agents and the ability to enable persistent tumor hypoxia relief can enable multiple rounds of PDT, which results in significantly enhanced immune responses by multiround stimulation. Further combination of such gel-based multiround PDT with anticytotoxic T-lymphocyte antigen-4 checkpoint blockade offers not only the abscopal effect to inhibit growth of distant tumors but also effective long-term immune memory protection from rechallenged tumors. Therefore, such a light-triggered in situ gelation system by a single-dose injection can enable greatly enhanced photoimmunotherapy by means of repeated stimulations.

Locally Trapping the C-C Chemokine Receptor Type 7 by Gene Delivery Nanoparticle Inhibits Lymphatic Metastasis Prior to Tumor Resection.

Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype. Currently, no targeted treatment is available for TNBC, and the most common clinical therapy is tumor resection, which often promotes metastasis risks. Strong evidence suggests that the lymphatic metastasis is mediated by the C-C chemokine receptor type 7 (CCR7)/C-C motif chemokine ligand 21 crosstalk between tumor cells and the lymphatic system. It is hypothesized that CCR7 is a key immune modulator in the tumor microenvironment and the local blockade of CCR7 could effectively inhibit TNBC lymphatic metastasis. Accordingly, a plasmid encoding an antagonistic CCR7 affinity protein-CCR7 trap is delivered by tumor targeting nanoparticles in a highly metastatic 4T1 TNBC mouse model. Results show that CCR7 traps are transiently expressed, locally disrupt the signaling pathways in the tumor site, and efficiently inhibit TNBC lymphatic metastasis, without inducing immunosuppression as observed in systemic therapies using CCR7 monoclonal antibody. Significantly, upon applying CCR7 trap therapy prior to tumor resection, a 4T1 TNBC mouse model shows good prognosis without any further metastasis and relapse. In addition, CCR7 trap therapy efficiently inhibits the lymphatic metastasis in a B16F10 melanoma mouse model, indicating its great potential for various metastatic diseases treatment.

Nanoparticle-Enhanced Radiotherapy to Trigger Robust Cancer Immunotherapy.

External radiotherapy is extensively used in clinic to destruct tumors by locally applied ionizing-radiation beams. However, the efficacy of radiotherapy is usually limited by tumor hypoxia-associated radiation resistance. Moreover, as a local treatment technique, radiotherapy can hardly control tumor metastases, the major cause of cancer death. Herein, core-shell nanoparticles based poly(lactic-co-glycolic) acid (PLGA) are fabricate, by encapsulating water-soluble catalase (Cat), an enzyme that can decompose H2 O2 to generate O2 , inside the inner core, and loading hydrophobic imiquimod (R837), a Toll-like-receptor-7 agonist, within the PLGA shell. The formed PLGA-R837@Cat nanoparticles can greatly enhance radiotherapy efficacy by relieving the tumor hypoxia and modulating the immune-suppressive tumor microenvironment. The tumor-associated antigens generated postradiotherapy-induced immunogenic cell death in the presence of such R837-loaded adjuvant nanoparticles will induce strong antitumor immune responses, which together with cytotoxic T-lymphocyte associated protein 4 (CTLA-4) checkpoint blockade will be able to effectively inhibit tumor metastases by a strong abscopal effect. Moreover, a long term immunological memory effect to protect mice from tumor rechallenging is observed post such treatment. This work thus presents a unique nanomedicine approach as a next-generation radiotherapy strategy to enable synergistic whole-body therapeutic responses after local treatment, greatly promising for clinical translation.

Photosensitizer-crosslinked in-situ polymerization on catalase for tumor hypoxia modulation & enhanced photodynamic therapy.

Tumor hypoxia is known to be one of critical factors that aggravate the tumor resistance to photodynamic therapy (PDT) in which oxygen is essential for tumor destruction. Herein, catalase, an enzyme to trigger hydrogen peroxide (H2O2) decomposition, is modified by in-situ free radical polymerization, using meso-tetra(p-hydroxyphenyl) porphine (THPP) as the cross-linker to enable condensed grafting of short polyethylene glycol (PEG) chains on the protein surface as a permeable brush-like safeguard. The formulated catalase-entrapped nanocapsules (CAT-THPP-PEG) with enhanced enzyme stability can be labeled with 99mTc4+, a radioisotope ion that is chelated by the porphyrin structure of THPP, to allow in vivo single-photon emission computed tomography (SPECT) imaging. It is found that such CAT-THPP-PEG nanoparticles exhibit efficient tumor passive retention after intravenous injection, and are able to greatly relieve tumor hypoxia by triggering the decomposition of tumor endogenous H2O2 into oxygen. With THPP functioning as a photosensitizer, in vivo PDT is further conducted, achieving a remarkable antitumor therapeutic effect. This work presents an enzyme modification strategy by in-situ polymerization with photosensitizer as the cross-linker to develop multifunctional nano-theranostics with strengthened enzymatic stability, efficient tumor passive homing, SPECT imaging capability, enhanced PDT efficacy as well as decreased immunogenicity, promising for clinical translation.

Cancer Cell Membrane-Coated Adjuvant Nanoparticles with Mannose Modification for Effective Anticancer Vaccination.

Tumor vaccines for cancer prevention and treatment have attracted tremendous interests in the area of cancer immunotherapy in recent years. In this work, we present a strategy to construct cancer vaccines by encapsulating immune-adjuvant nanoparticles with cancer cell membranes modified by mannose. Poly(d,l-lactide- co-glycolide) nanoparticles are first loaded with toll-like receptor 7 agonist, imiquimod (R837). Those adjuvant nanoparticles (NP-R) are then coated with cancer cell membranes (NP-R@M), whose surface proteins could act as tumor-specific antigens. With further modification with mannose moiety (NP-R@M-M), the obtained nanovaccine shows enhanced uptake by antigen presenting cells such as dendritic cells, which would then be stimulated to the maturation status to trigger antitumor immune responses. With great efficacy to delay tumor development as a prevention vaccine, vaccination with such NP-R@M-M in combination with checkpoint-blockade therapy further demonstrates outstanding therapeutic efficacy to treat established tumors. Therefore, our work presents an innovative way to fabricate cancer nanovaccines, which in principle may be applied for a wide range of tumor types.

Smart Nanoreactors for pH-Responsive Tumor Homing, Mitochondria-Targeting, and Enhanced Photodynamic-Immunotherapy of Cancer.

Photodynamic therapy (PDT) is an oxygen-dependent light-triggered noninvasive therapeutic method showing many promising aspects in cancer treatment. For effective PDT, nanoscale carriers are often needed to realize tumor-targeted delivery of photosensitizers, which ideally should further target specific cell organelles that are most vulnerable to reactive oxygen species (ROS). Second, as oxygen is critical for PDT-induced cancer destruction, overcoming hypoxia existing in the majority of solid tumors is important for optimizing PDT efficacy. Furthermore, as PDT is a localized treatment method, achieving systemic antitumor therapeutic outcomes with PDT would have tremendous clinical values. Aiming at addressing the above challenges, we design a unique type of enzyme-encapsulated, photosensitizer-loaded hollow silica nanoparticles with rationally designed surface engineering as smart nanoreactors. Such nanoparticles with pH responsive surface coating show enhanced retention responding to the acidic tumor microenvironment and are able to further target mitochondria, the cellular organelle most sensitive to ROS. Meanwhile, decomposition of tumor endogenous H2O2 triggered by those nanoreactors would lead to greatly relieved tumor hypoxia, further favoring in vivo PDT. Moreover, by combining our nanoparticle-based PDT with check-point-blockade therapy, systemic antitumor immune responses could be achieved to kill nonirradiated tumors 1-2 cm away, promising for metastasis inhibition.