A hypoxic and acidic tumor microenvironment (TME) plays a significant role in cancer development through complex cellular signaling networks, and it is thus challenging to completely eradicate tumors via monotherapy. Here, PEGylated CoFe 2 O 4 nanoflowers (CFP) with multiple enzymatic activities, serving as bioreactors responsive to TME cues, were synthesized via a typical solvothermal method for augmented sonodynamic therapy (SDT) and chemodynamic therapy (CDT) with elicitation of robust immune response. The CFP occupying multivalent elements (Co 2+/3+ , Fe 2+/3+ ) exhibited strong Fenton-like and catalase-like activity. In another aspect, CFP itself is a brand-new sonosensitizer for highperformance SDT based on ultrasound-triggered electron (e − )/ hole (h + ) pair separation from the energy band with promptness and high efficiency. With efficient enrichment in tumorous tissue as revealed by magnetic resonance imaging, CPF could generate • OH for CDT relying on Fenton-like reactions. Moreover, catalase-mimicking CFP could react with endogenous H 2 O 2 to generate molecular oxygen, and high O 2 level may promote the production of 1 O 2 for SDT. What's more, the reactive oxygen species obtained from combined SDT/CDT could efficiently trigger immunogenic cell death through a synergistic therapy based on the elicitation of antitumor immunity with the aid of an immune checkpoint blockade for the sake of suppressing primary and distant tumors as well as lung metastasis. Taken together, this paradigm delivers useful insights for developing in-coming nanocomposites based on cobalt ferrite for cancer theranostics.

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Indocyanine green (ICG) is capable of inducing a photothermal effect and the production of cytotoxic reactive oxygen species for cancer therapy. However, the major challenge in applying ICG molecules for antitumor therapy is associated with their instability in aqueous conditions and rapid clearance from blood circulation, which causes insufficient bioavailability at the tumor site. Herein, we conjugated ICG molecules with Prussian blue nanoparticles enclosing a Fe3O4 nanocore, which was facilitated by cationic polyethyleneimine via electrostatic adsorption. The nanocarrier-loaded ICG formed stable aggregates that enhanced cellular uptake and prevented fluorescence quenching. Moreover, the strong superparamagnetism of the Fe3O4 core in the obtained nanocomposites further improved cellular internalization of the drugs guided by a localized magnetic field. The therapeutic efficacy of this nanoplatform was evaluated using tumor models established in nude mice, which demonstrated remarkable tumor ablation in vivo due to strong photothermal/photodynamic effects. This study provides promising evidence that this multifunctional nanoagent might function as an efficient mediator for combining photothermal and photodynamic cancer therapy.Electronic supplementary materialThe online version of this article (10.1007/s40820-018-0227-z) contains supplementary material, which is available to authorized users.

Regenerated silk fibroin (SF) is a type of natural biomacromolecules with outstanding biocompatibility and biodegradability. However, stimulus-responsive SF-based nanocomplex has seldom been reported for application in tumor diagnosis and therapy.Methods: As a proof-of-concept study, a multifunctional SF@MnO2 nanoparticle-based platform was strategically synthesized using SF as a reductant and a template via a biomineralization-inspired crystallization process in an extremely facile way. Because of their mesoporous structure and abundant amino and carboxyl terminal residues, SF@MnO2 nanoparticles were co-loaded with a photodynamic agent indocyanine green (ICG) and a chemotherapeutic drug doxorubicin (DOX) to form a SF@MnO2/ICG/DOX (SMID) nanocomplex.Results: The obtained product was highly reactive with endogenous hydrogen peroxide (H2O2) in tumor microenvironment, which was decomposed into O2 to enhance tumor-specific photodynamic therapy (PDT). Moreover, SMID nanocomplex produced a strong and stable photothermal effect upon near-infrared (NIR) irradiation for photothermal therapy (PTT) owing to the distinct photothermal response of SF@MnO2 and stably conjugated ICG. The concurrent NIR fluorescence and magnetic resonance (MR) imaging in vivo both indicated effective tumor-specific enrichment of SMID nanoparticles via enhanced permeability and retention (EPR) effect. Animal studies further verified that SMID nanoparticles remarkably improved tumor inhibitive efficacy through combination PTT/PDT/chemotherapy with minimal systemic toxicity or adverse effect.Conclusion: This study demonstrated the promising potential of SF-based nanomaterial to address some of the key challenges in cancer therapy due to unfavorable tumor microenvironment for drug delivery.

Polymeric microneedles have attracted increasing attention as a minimally invasive platform for delivering drugs or vaccines in a more patient-friendly manner. However, traditional microfabrication techniques using negative molds with needle-shaped cavities usually require cumbersome centrifugation and vacuum degassing processes, which have restricted the scaled-up mass production of polymeric microneedles. Herein, a novel polydimethylsiloxane (PDMS)-based negative mold with cavities packed with silk fibroin scaffold is developed for rapid fabrication of polymeric microneedles, which comprise primarily the composition of poly-(ethylene glycol) diacrylate (PEGDA) and sucrose as the needle matrix. Fibroin scaffolds can instantly adsorb prepolymer solution due to capillary force, and subsequently initiate the formation of microneedles via photoinduced polymerization. Based on three types of model drugs, including Rhodamine B (RhB), indocyanine green (ICG), and doxorubicin (DOX), the fabricated PEGDA/ sucrose microneedles can realize effective transdermal delivery and controllable release of therapeutic molecules by regulating the sucrose content. The presented method provides a simple strategy for quick fabrication of polymeric microneedles toward transdermal drug delivery applications.

Environmental stimuli, including pH, light, and temperature, have been utilized for activating controlled drug delivery to achieve efficient antitumor therapeutics while minimizing undesirable side effects. In this study, a multifunctional nanoplatform based on hollow mesoporous copper sulfide nanoparticles (H-CuS NPs) was developed by loading the interior cavity of the NPs with a drug-loaded phase-change material (PCM, 1-tetradecanol). Doxorubicin (DOX) and chlorin e6 (Ce6) were selected as the model chemotherapeutic drug and photosensitizer, respectively, which were encapsulated in H-CuS NPs via the PCM to form H-CuS@PCM/DOX/Ce6 (HPDC) NPs. When exposed to near infrared laser irradiation, this nanocomplex could produce a strong photothermic effect and thus induce the controlled release of DOX and Ce6 from the melting PCM. Subsequently, the DOX-mediated chemotherapeutic effect and Ce6-mediated photodynamic effect further contributed to enhanced tumor eradication. The efficacy of this multimodal cancer treatment combining chemo-, photothermal, and photodynamic therapies was systematically evaluated both in vitro and in vivo using a 4T1 mouse mammary tumor cell line and a mouse model bearing breast cancer. Moreover, this nanoplatform exhibited minimal systemic toxicity and good hemocompatibility and may provide an effective strategy for the delivery of multiple therapeutic agents and application of multimodal cancer treatments.

Hollow mesoporous Prussian blue nanoparticles were exploited for high dose drug loading and multimodal tumor theranostics.

Multiple therapeutic modalities, such as photodynamic (PDT) and photothermal (PTT) therapies, have been jointly applied to produce a synergistic effect for tumor eradication based on the hyperthermia and generation of reactive oxygen species (ROS) mediated by photoactive agents. Effective delivery of highly efficient photosensitizers and photothermal agents is the key for combination of PDT/PTT. Herein, we propose a strategy to functionalize Prussian blue (PB) nanoparticles (NPs) with Chlorin e6 (Ce6)-imbedded erythrocyte membrane vesicles. This nanoplatform can address the major issues of these two capable photoactive agents, such as limited biocompatibility, lack of functional chemical groups, and poor bioavailability due to rapid blood clearance or self-aggregation. Specifically, PB NPs were packaged within Ce6-imbedded erythrocyte membrane vesicles, named as PB@RBC/Ce6 NPs, to take advantage of both biological functions of natural erythrocyte membranes and the unique physicochemical properties of synthetic nanoagents. Compared to bare PB NPs or free Ce6, PB@RBC/Ce6 NPs exhibited considerably enhanced cellular uptake and accumulation in tumoral tissues. Moreover, the PB@RBC/Ce6 NP-mediated PDT/PTT combination therapies produced a notable effect in boosting the necrosis and late apoptosis of tumor cells in vitro, and further showed a synergistic therapeutic effect against an orthotopic tumor model in vivo.