NIR-Light-Activated Ratiometric Fluorescent Hybrid Micelles for High Spatiotemporally Controlled Biological Imaging and Chemotherapy.

Intelligent-responsive imaging-therapy strategy has shown great significance for biomedicine. However, it is still a challenge to construct spatiotemporally controlled imaging-therapy systems triggered by near infrared (NIR) light. In this work, NIR-light-activated ratiometric fluorescent hybrid micelles (RFHM) are prepared via the co-assembly of upconversion nanoparticles (UCNPs), doxorubicin (DOX), and UV-light-responsive amphiphilic block copolymer for the spatiotemporally controlled imaging and chemotherapy. Upon NIR light irradiation, UCNPs can convert NIR light to UV light. The emitted UV light induces the photoreaction of copolymer to further trigger ratiometric fluorescence imaging and degradation of hybrid micelles, resulting in rapid DOX release from hybrid micelles for antitumor therapy. The animal experiments reveal that NIR light can not only remotely regulate the ratiometric fluorescence imaging of RFHM in tumor tissue, but also trigger DOX release from RFHM to inhibit tumor growth. Therefore, this study provides a new strategy to achieve high spatial-temporal-controlled biological imaging and chemotherapy.

Kinetic Control of Length and Morphology of Segmented Polymeric Nanofibers in Microfluidic Chips.

In this work, we report an approach to prepare segmented polymer nanofibers (SPNFs) composed of rodlike subunits by kinetically controlled self-assembly of polystyrene-b-poly(4-vinylpyridine)-based supramolecules in microfluidic chips. The length and morphology of the SPNFs could be effectively adjusted by changing the total flow rate (Vtotal) and the molar ratio (x) of 4-vinylpyridine (4VP) unit to a hydrogen-bonding molecule, 3-n-pentadecyphenol. Moreover, the subunits of SPNFs could transform from short rods to spheres when the interfacial tension between PS core and solvent increased. On the contrary, the SPNFs elongated along the major axis when the interfacial tension decreased. This work not only offers mechanism insights into the hierarchical self-assembly of block copolymer-based supramolecules but also provides a versatile and effective method for kinetically controlling the hierarchical structures of assemblies.

Flow-Induced Micellar Morphological Transformation in Microfluidic Chips under Nonequilibrium State: From Aggregates to Spherical Micelles.

Self-assembly of block copolymers (BCPs) in microfluidic chips is a versatile yet effective route to produce micellar aggregates with various controllable sizes and morphologies. In this study, the morphological transformation of the BCP of polystyrene-b-poly(4-vinylpyridine) (PS-b-P4VP) assemblies from irregular aggregates to multicompartment micelles and ultimately to ordered spherical micelles is demonstrated in microfluidic chips. Our experimental and computational simulation results indicate that the transverse diffusion of solvents plays an important role in the morphological transformation of PS-b-P4VP assemblies in the confined flow condition. We find that the mixing time (tmix) between a BCP/tetrahydrofuran (THF) solution and water affects the morphological transformation. Micellar morphologies are intended to transform from aggregates to ordered spherical structures under a relatively long mixing time (tmix). In addition, it is observed that the size of the micelles decreases with the increase of the flow velocity ratio by tuning the hydrodynamic conditions of the flows. Moreover, by adjusting the initial polymer solution concentration, temperature, and weight fraction of the introduced homopolystyrene (hPS), which can affect the viscosity of the BCP solution, the flow diffusion in the microfluidic chip and the resulted micellar structures can also be readily adjusted. The current study provides a new flow-driven method to adjust the micellar ordered structural transformation under the nonequilibrium state.

Polymer-Upconverting Nanoparticle Hybrid Micelles for Enhanced Synergistic Chemo-Photodynamic Therapy: Effects of Emission-Absorption Spectral Match.

Chemo-photodynamic combined therapy is promising in cancer treatment, although low tissue penetration of visible light for activating photosensitizers (e.g., chlorin e6, Ce6) limited its broad applications. Combination of upcoverting nanoparticles (UCNPs) with the photosensitizers endows us with the possibility to utilize highly tissue penetrable near-infrared light; nevertheless, the mismatch between absorption of common photosensitizers (λabs, mainly red) and emission of UCNPs (λem, mainly green) resulted in low energy utilization and unsatisfied therapeutic efficacy in the current UCNP-PDT (photodymanic therapy) platforms. To resolve this problem, herein, we construct polymer-UCNP hybrid micelles (PUHMs) for codelivery of doxorubicin (DOX) and Ce6, and systemically studied the effects of spectral match between λem of UCNPs and λabs of Ce6 on efficiency of synergistic chemo-photodynamic therapy. Compared with spectrally mismatched PUHMs, the spectrally matched PUHMs can significantly enhance the utilization efficiency of upconverted emission energy to activate the photosensitizers and generate more reactive oxygen species (ROS) for enhanced photodynamic therapy. Meanwhile, as the assembled structure of PUHMs can be destroyed by the oxidation of ROS upon 980 nm laser irradiation because of the hydrophobic-hydrophilic transformation of poly(propylene sulfide) (PPS) segment, the spectrally matched PUHMs triggered faster release of DOX, thus resulting in more effective chemotherapy. As a result, the spectrally matched PUHMs induced more prominent cytotoxicity and superior synergistic therapeutic effect for cancer cells in vitro. Our results demonstrated that such spectrally matched PUHMs provide us with an effective strategy for photodynamic-chemo synergistic therapy.

Cell-Penetrating Peptides Transport Noncovalently Linked Thermally Activated Delayed Fluorescence Nanoparticles for Time-Resolved Luminescence Imaging.

Luminescent probes and nanoparticles (NPs) with long excited state lifetimes are essential for time-resolved biological imaging. Generally, cell membranes are physiological barriers that could prevent the uptake of many unnatural compounds. It is still a big challenge to prepare biocompatible imaging agents with high cytomembrane permeability, especially for nonmetallic NPs with long-lived luminescence. Herein, an amphiphilic cell-penetrating peptide, F6G6(rR)3R2, was designed to transport hydrophobic fluorophores across cellular barriers. Three classical thermally activated delayed fluorescence (TADF) molecules, 4CzIPN, NAI-DPAC, and BTZ-DMAC, could self-assemble into well-dispersed NPs with F6G6(rR)3R2 in aqueous solution. These NPs showed low cytotoxicity and could penetrate membranes easily. Moreover, long-lived TADF enabled them to be used in time-resolved luminescence imaging in oxygenic environments. These findings greatly expanded the applications of cell-penetrating peptides for delivery of molecules and NPs by only noncovalent interactions, which were more flexible and easier than covalent modifications.

Regulating Block Copolymer Assembly Structures in Emulsion Droplets through Metal Ion Coordination.

In this report, we demonstrate the metal ion coordination-induced morphological transition of block copolymer assemblies under three-dimensional (3D) confinement. Polystyrene- block-poly(4-vinyl pyridine) (PS- b-P4VP) aggregates with various morphologies can be obtained by emulsion-solvent evaporation in the presence of metal ions (e.g., Pb(II) or Fe(III) ions) in the aqueous phase. Due to the coordination interaction between 4VP units and metal ions, the overall shape, internal structure, and surface composition of the particles can be tailored by varying the type and concentration of the metal ions. For example, when Pb(II) ions were employed, morphological transition of the assemblies occurred due to the formation of P4VP-Pb(II) complexes. More interestingly, when Fe(III) ions were added, hydrolysis of Fe(III) caused the reduction of the pH value of the aqueous phase, leading to the protonation of 4VP units. As a result, interfacial instability took place to trigger the splitting of emulsion droplets and then formation of nanosized micelles. Therefore, metal ion coordination is a facile strategy to tune the structure of assemblies under 3D confinement and offers an alternative approach for the design of organic-inorganic hybrid assemblies with well-tunable structures.

Photothermal Effect-Triggered Drug Release from Hydrogen Bonding-Enhanced Polymeric Micelles.

Incorporation of noncovalent interactions into hydrophobic cores of polymeric micelles provides the micelles with enhanced physical stability and drug loading efficiency, however, it also creates obstacles for drug release due to the strong interactions between carriers and drugs. Herein, a series of amphiphilic block copolymers based on poly(ethylene glycol)- b-poly(l-lysine) (mPEG- b-PLL) with similar chemical structures, while different hydrogen bonding donors (urethane, urea, and thiourea groups) are synthesized, and their capacities for codelivery of anticancer drug (e.g., doxorubicin) and photothermal agent (e.g., indocyanine green) are investigated. The resulting hybrid micelles display decreased critical micelle concentrations (CMCs) and enhanced micelle stabilities due to the hydrogen bonding between urea groups in the polymers. Moreover, the strong hydrogen bonds between the urea/thiourea groups and drugs provide the carriers with enhanced drug loading efficiencies, decreased micelle sizes, however, slower drug release profiles as well. When exposed to the near-infrared laser irradiation, destabilization of the hydrogen bonding through photothermal effect triggers fast and controlled drug releases from the micelles, which dramatically promotes the aggregation of the drugs in the nuclei, resulting in an enhanced anticancer activity. These results demonstrate that the hydrogen bonding-enhanced micelles are promising carriers for controllable chemo-photothermal synergistic therapy.

Cascade-amplified self-immolative polymeric prodrug for cancer therapy by disrupting redox homeostasis.

The amplification of reactive oxygen species (ROS) generation and glutathione (GSH) depletion in cancer cells represents a promising strategy to disrupt redox homeostasis for cancer therapy. Quinone methide and its analogs (QM) have recently been recognized as potential GSH scavengers for anticancer applications; however, an effective QM prodrug is yet to be developed. In this study, we prepare a self-immolative polymeric prodrug (SPP), which could be selectively degraded to generate large quantities of QMs in cancer cells during the spontaneous stepwise head-to-tail degradation of SPP. The amphiphilic SPP is self-assembled into nano-sized micelles, allowing for encapsulating 2-methoxy-ß-estradiol (2ME), an anticancer drug that produces a large amount of intracellular ROS. When SPP@2ME, as the cascade-amplified prodrug, is treated on the cancer cells, 2ME is rapidly released at the ROS-rich intracellular environment by degradation of SPP, thus generating more ROS that triggers the degradation of more SPP chains. Such a domino-like cascade-amplified feedback loop significantly amplifies oxidative stress and disrupts the redox homeostasis in cancer cells. This unique strategy provides synergistic anticancer therapeutic efficacy and demonstrates an important perception in innovative and precise nanomedicine.

Self-immolative polymer-based immunogenic cell death inducer for regulation of redox homeostasis.

Doxorubicin (DOX), widely used as an anticancer drug, is considered an immunogenic cell death (ICD) inducer that enhances cancer immunotherapy. However, its extended application as an ICD inducer has been limited owing to poor antigenicity and inefficient adjuvanticity. To enhance the immunogenicity of DOX, we prepare a reactive oxygen species (ROS)-responsive self-immolative polymer (R-SIP) that can efficiently destroy redox homeostasis via self-immolation-mediated glutathione depletion in cancer cells. Owing to its amphiphilic nature, R-SIP self-assemble into nano-sized particles under aqueous conditions, and DOX is efficiently encapsulated inside the nanoparticles by a simple dialysis method. Interestingly, when treated with 4T1 cancer cells, DOX-encapsulated R-SIP (DR-SIP) induces the phosphorylation of eukaryotic translation initiation factor 2α and overexpression of ecto-calreticulin, resulting in endoplasmic reticulum-associated ICD. In addition, DR-SIP contributes to the maturation of dendritic cells by promoting the release of damage-associated molecular patterns (DAMPs) from cancer cells. When intravenously administered to tumor-bearing mice, DR-SIP remarkably inhibits tumor growth compared with DOX alone. Overall, DR-SIP may have the potential to elicit an immune response as an ICD inducer.

Recent progress in nitric oxide-generating nanomedicine for cancer therapy.

Nitric oxide (NO) is an endogenous, multipotent biological signaling molecule that participates in several physiological processes. Recently, exogenous supplementation of tumor tissues with NO has emerged as a potential anticancer therapy. In particular, it induces synergistic effects with other conventional therapies (such as chemo-, radio-, and photodynamic therapies) by regulating the activity of P-glycoprotein, acting as a vascular relaxant to relieve tumor hypoxia, and participating in the metabolism of reactive oxygen species. However, NO is highly reactive, and its half-life is relatively short after generation. Meanwhile, NO-induced anticancer activity is dose-dependent. Therefore, the targeted delivery of NO to the tumor is required for better therapeutic effects. In the past decade, NO-generating nanomedicines (NONs), which enable sustained and specific NO release in tumor tissues, have been developed for enhanced cancer therapy. This review describes the recent efforts and preclinical achievements in the development of NON-based cancer therapies. The chemical structures employed in the fabrication of NONs are summarized, and the strategies involved in NON-based cancer therapies are elaborated.

Dissolving microneedles for long-term storage and transdermal delivery of extracellular vesicles.

Extracellular vesicles (EVs) have shown great potential in disease diagnosis and treatment; however, their clinical applications remain challenging due to their unsatisfactory long-term stability and the lack of effective delivery strategies. In this study, we prepared human adipose stem cell-derived EV (hASC-EV)-loaded hyaluronic acid dissolving microneedles (EV@MN) to investigate the feasibility of EVs for their clinical applications. The biological activities of the EVs in this formulation were maintained for more than six months under mild storage conditions, especially at temperatures lower than 4 °C. Moreover, the EV@MN enabled precise and convenient intradermal delivery for sustained release of EVs in the dermis layer. Therefore, EV@MN significantly improved the biological functions of hASC-EVs on dermal fibroblasts by promoting syntheses of proteins for the extracellular matrix such as collagen and elastin, enhancing fibroblast proliferation, and regulating the phenotype of fibroblast, compared with other administration methods. This research revealed a possible and feasible formulation for the clinical application of EVs.

A Tissue-Tended Mycophenolate-Modified Nanoparticle Alleviates Systemic Lupus Erythematosus in MRL/Lpr Mouse Model Mainly by Promoting Local M2-Like Macrophagocytes Polarization.

Background: Mycophenolate mofetil (MMF), for which the bioactive metabolite is mycophenolic acid (MPA), is a frequently used immunosuppressant for systemic lupus erythematosus (SLE). However, its short half-life and poor biodistribution into cells and tissues hinder its clinical efficacy. Our dextran mycophenolate-based nanoparticles (MPA@Dex-MPA NPs) have greatly improved the pharmacokinetics of MMF/MPA. We here tested the therapeutic efficacy of MPA@Dex-MPA NPs against SLE and investigated the underlying mechanism. Methods: The tissue and immune cell biodistributions of MPA@Dex-MPA NPs were traced using live fluorescence imaging system and flow cytometry, respectively. Serological proinflammatory mediators and kidney damage were detected to assess the efficacy of MPA@Dex-MPA NPs treatments of MRL/lpr lupus-prone mice. Immune cell changes in the kidney and spleen were further analyzed post-treatment via flow cytometry. Bone marrow-derived macrophages were used to investigate the potential mechanism. Results: MPA@Dex-MPA NPs exhibited superior therapeutic efficacy and safety in the MRL/lpr mice using significantly lower administration dosage (one-fifth) and frequency (once/3 days) compared to MMF/MPA used in ordinary practice. The overall prognosis of the mice was improved as they showed lower levels of serological proinflammatory mediators. Moreover, kidney injury was alleviated with reduced pathological signs and decreased urine protein-creatinine ratio. Further investigations of the underlying mechanism revealed a preferential penetration and persistent retention of MPA@Dex-MPA NPs in the spleen and kidney, where they were mostly phagocytosed by macrophages. The macrophages were found to be polarized towards a CD206+ M2-like phenotype, with a downregulation of surface CD80 and CD40, and reduced TNF-α production in the spleen and kidney and in vitro. The expansion of T cells was also significantly inhibited in these two organs. Conclusion: Our research improved the efficacy of MPA for MRL/lpr mice through synthesizing MPA@Dex-MPA NPs to enhance its tissue biodistribution and explored the possible mechanism, providing a promising strategy for SLE therapy.

Gold nanoparticle-guarded large-pore mesoporous silica nanocomposites for delivery and controlled release of cytochrome c.

Efficient delivery of active proteins to specific cells and organs is one of the most important issues in medical applications. However, in most cases, proteins without appropriate carriers face numerous barriers when delivered to the target, due to their unsatisfied properties, such as poor stability, short half-life, and low membrane permeability. Herein, we have presented a large-pore mesoporous silica nanoparticle (LPMSN)-based protein delivery system. LPMSNs were obtained with ethyl acetate as a pore expander. A 2,3-dimethylmaleamic acid-containing silane coupling agent was modified on LPMSNs to provide pH-triggered charge reversal. After Cytochrome c (CC) was encapsulated in the large pores of LPMSNs, amino-terminated polyethylene glycol-modified gold nanoparticles (AuNPs) served as gateguards to cap the tunnels of LPMSNs and to avoid the leakage of CC. Above nanocomposites exhibited the capability to deliver active CC into cancer cells, charge reversal-induced protein release, as well as to initiate the apoptosis machinery of cancer cells in vitro. Importantly, the nanocomposites significantly inhibited tumor growth and extended survival rate without obvious side effects. This study provides a smart and efficient protein delivery platform with good safety profiles for efficacious tumor protein therapy in vivo.

Acitretin-Conjugated Dextran Nanoparticles Ameliorate Psoriasis-like Skin Disease at Low Dosages.

Psoriasis is a common chronic inflammatory skin disease mainly characterized by keratinocyte hyperproliferation and massive infiltration of inflammatory immune cells. Acitretin (ACT), an FDA-approved first-line systemic drug for psoriasis treatment, could suppress the proliferation of keratinocytes and downregulate the expression of inflammatory cytokines by modulating signal transducer and activator of transcription (STAT) signaling pathways. However, dose-dependent side effects of ACT limit its long-term administration in the clinic. Therefore, improving the therapeutic efficacy of ACT to reduce clinical dosage will benefit the patients. Here, we develop ACT-conjugated dextran nanoparticles (ACT-Dex NPs) and evaluated the potential for psoriasis treatment. Our results indicate that ACT-Dex NPs ameliorate psoriasis-like skin disease significantly at a low dosage which does not cause side effects, while neat ACT drugs at an equivalent dosage provide much less benefit. Moreover, we demonstrate that ACT-Dex NPs suppress keratinocyte proliferation more efficiently than neat ACT by enhancing the inhibitory effect on STAT3 phosphorylation. Thus, the proposed ACT-Dex NPs provide an effective and safe option for psoriasis treatment.

Polysaccharide mycophenolate-based nanoparticles for enhanced immunosuppression and treatment of immune-mediated inflammatory diseases.

Immune-mediated inflammatory diseases (IMIDs) are characterized by immune dysregulation and severe inflammation caused by the aberrant and overactive host immunological response. Mycophenolic acid (MPA)-based immunosuppressive drugs are potential treatments for IMIDs because of their mild side-effect profile; however, their therapeutic effects are limited by the high albumin binding rate, unsatisfactory pharmacokinetics, and undefined cellular uptake selectivity. Methods: Polysaccharide mycophenolate was synthesized by conjugating MPA molecules to dextran (a typical polysaccharide widely used in drug delivery) and encapsulated extra free MPA molecules to fabricate MPA@Dex-MPA nanoparticles (NPs). The efficacy of these NPs for mediating immunosuppression and treatment of IMIDs was evaluated in imiquimod-induced psoriasis-like skin inflammation in Balb/c mice, a representative IMID model. Results: The MPA@Dex-MPA NPs exhibited high MPA loading efficiency, low albumin binding rates, and sustained MPA release, resulting in improved pharmacokinetics in vivo. Compared to free MPA, MPA@Dex-MPA NPs induced more robust therapeutic effects on IMIDs. Mechanistic studies indicated that MPA@Dex-MPA NPs were primarily distributed in dendritic cells (DCs) and significantly suppressed the overactivated DCs in vivo and in vitro. Furthermore, the recovered DCs rehabilitated the IL-23/Th17 axis function and significantly ameliorated imiquimod-induced psoriasis-like skin inflammation. Importantly, MPA@Dex-MPA NPs showed favorable safety and biocompatibility in vivo. Conclusion: Our results indicated the polysaccharide mycophenolate-based NPs to be highly promising for IMID treatment.

Hypoxia-responsive nanoparticles for tumor-targeted drug delivery.

Hypoxia is a negative prognostic indicator of solid tumors. Increasing evidence indicates that the intratumoral hypoxic microenvironment is strongly related to enhanced tumor aggressiveness, decreased therapeutic effect and poor prognosis of chemotherapy, radiotherapy (RT), and photodynamic therapy (PDT). However, due to an unusual gene expression profile and abnormal metabolism, enzymes responsible for reduction reactions or electron donation are highly reactive in hypoxic tumor cells and provide the possibility of exploiting targeted drug delivery systems for cancer therapy. Taking advantage of the specific bioreductive microenvironments in hypoxic tumors, researchers have recently developed several hypoxia-responsive nanoparticles (HR-NPs) for targeted cancer therapy. In this review, the hypoxia-responsive molecular structures that were employed to construct HR-NPs are presented. Furthermore, the strategies to make use of these HR-NPs, and the recent advances in HR-NPs for efficient tumor-targeted drug delivery and cancer therapy are highlighted.

Hyaluronidase-Functionalized Silica Nanocarrier for Enhanced Chemo-Immunotherapy through Inducing Immunogenic Cell Death.

The chemo-immunotherapy has become a highly prospective method for cancer treatment, and it has been known that chemotherapeutic drugs [e.g., doxorubicin (DOX)] could trigger antitumor immune responses. Yet, insufficient tumor penetrability and weak immunogenic cell death (ICD) severely limits the therapeutic effect of chemo-immunotherapy against cancer. Herein, we report the design of DOX-loaded silica nanocarriers (DOX@HMSPHs) with hyaluronidase functionalization, which could increase the permeability of drug and induce enhanced ICD effect through the degradation of hyaluronic acid (HA) in the extracellular matrix (ECM). Interestingly, the controlled release of DOX from DOX@HMSPHs in the acidic microenvironment induced ICD of tumor cells to release tumor antigens and damage-associated molecular patterns, promoting the antigen-presentation of dendritic cells (DCs) and the activation of specific tumor immunity. Moreover, HMSPHs could be used as an immune adjuvant to promote maturation of DCs, thereby promoting the activation of tumor infiltrating cytotoxic T lymphocytes. This strategy presents a concept to improve the efficacy of chemo-immunotherapy through degradation of HA in the ECM.

Transdermal delivery of rapamycin with poor water-solubility by dissolving polymeric microneedles for anti-angiogenesis.

Angiogenesis plays an important role in the occurrence and development of skin tumors and vascular anomalies (VAs). Many drugs have been adopted for the inhibition of angiogenesis, among which rapamycin (RAPA) possesses good application prospects. However, the clinical potential of RAPA for VAs is limited by its poor solubility, low bioavailability, and high cytotoxicity. To extend its application prospect for VAs treatment, in this study, we develop RAPA-loaded dissolving polymeric microneedles (RAPA DMNs) made of polyvinylpyrrolidone (PVP) due to its excellent solubilizing ability. RAPA DMNs are shown to have sufficient mechanical strength to overcome the skin barrier of the stratum corneum and could deliver RAPA to a depth of 200 µm. The microneedle shafts completely dissolve and 80% of the drug could be released within 10 min after insertion ex vivo. The DMNs-penetrated mice skin could repair itself within 4 h after the application of RAPA DMNs. RAPA DMNs also show good anti-angiogenic effect by inhibiting the growth of human umbilical vein endothelial cells (HUVECs) and decreasing the secretion of vascular endothelial growth factor (VEGF). Therefore, RAPA DMNs promisingly provide a safe and efficient approach for VAs treatment.

Synergistic chemo-photodynamic therapy mediated by light-activated ROS-degradable nanocarriers.

The combination of chemotherapy and photodynamic therapy (PDT) using polymeric nanocarriers is effective for improving therapeutic efficiency against cancer. Yet, in most reported cases, due to the lack of synergistic mechanisms, chemotherapy and PDT work independently rather than synergistically-the functions of chemotherapeutic drugs and photosensitizers in nanocarriers are independent when they are delivered to cancer cells. Here, we demonstrate the construction of reactive oxygen species (ROS)-degradable nanoparticles (NPs) based on phenylboronic pinacol ester-conjugated dextran (PPE-Dex) through a membrane-extrusion emulsification approach for the co-delivery of anticancer drug (e.g., doxorubicin, Dox) and photosensitizer (e.g., chlorin e6, Ce6). When exposed to 655 nm laser irradiation, ROS generated by encapsulated Ce6 not only induced a significant PDT effect in cancer cells, but also triggered the rapid oxidization and degradation of PPE-Dex, resulting in the quick release and enhanced intra-nuclei accumulation of Dox. In vitro cytotoxicity and combination index (CI) assay indicated that the PPE-Dex NPs offered remarkable synergistic therapeutic effects of Dox and Ce6 against cancer cells under irradiation. Furthermore, the drug release profiles can be well regulated by changing the irradiation time to satisfy different demands in various treatment programs. Our results demonstrated that such ROS-degradable polymeric NPs with light-activated disassembly capability are promising carriers for synergistic photodynamic-chemo therapy in cancer therapy.