A dual responsive nitric oxide / ß-lapachone co-delivery platform for redox imbalance-enhanced tumor therapy.

Nitric oxide (NO) / ß-Lapachone (Lap) combined therapy by causing oxidative stress is an effective tumor therapy strategy. Herein, a dual-responsive lipid nanoparticles (LNPs) LSNO for NO / Lap co-delivery were constructed from the zinc-coordinated lipid (DSNO(Zn)) and the hydrophobic drug Lap in the presence of helper lipids (DOPE and DSPE-PEG2000). The zinc-coordinated structure in LSNO might elevate the Zn2+ content in tumor cells, contributing to antioxidant imbalance. The fluorescent assays proved the light-triggered NO release and fluorescent self-reporting abilities of LSNO. In addition, the LNPs had good drug release behavior under high concentration of GSH, indicating the NO / drug co-delivery capacity. In vitro antitumor assays showed that the NO / Lap combination treatment group could induce more significant tumor cell growth inhibition and cell apoptosis than individual NO or Lap treatment. The following mechanism studies revealed that NO / Lap combination treatment led to distinct oxidative stress by producing reactive oxygen species (ROS) and peroxynitrite anion (ONOO-). On the other hand, the intracellular redox balance could be further disrupted by Lap-induced NADPH consumption and Zn2+ / NO-induced reductase activities downregulation, thus promoting the degree of cell damage. Besides, it was also found that NO and Lap could directly damage nuclear DNA and induce mitochondrial dysfunction, thereby leading to caspase-3 activation and tumor cell death. These results proved that LSNO could serve as a promising multifunctional tumor therapy platform.

Machine-Learning-Assisted Rational Design of Si─Rhodamine as Cathepsin-pH-Activated Probe for Accurate Fluorescence Navigation.

High-performance fluorescent probes stand as indispensable tools in fluorescence-guided imaging, and are crucial for precise delineation of focal tissue while minimizing unnecessary removal of healthy tissue. Herein, machine-learning-assisted strategy to investigate the current available xanthene dyes is first proposed, and a quantitative prediction model to guide the rational synthesis of novel fluorescent molecules with the desired pH responsivity is constructed. Two novel Si─rhodamine derivatives are successfully achieved and the cathepsin/pH sequentially activated probe Si─rhodamine─cathepsin-pH (SiR─CTS-pH) is constructed. The results reveal that SiR─CTS-pH exhibits higher signal-to-noise ratio of fluorescence imaging, compared to single pH or cathepsin-activated probe. Moreover, SiR─CTS-pH shows strong differentiation abilities for tumor cells and tissues and accurately discriminates the complex hepatocellular carcinoma tissues from normal ones, indicating its significant application potential in clinical practice. Therefore, the continuous development of xanthene dyes and the rational design of superior fluorescent molecules through machine-learning-assisted model broaden the path and provide more advanced methods to researchers.

Real-Time Monitoring of Tyrosine Hydroxylase Activity with a Ratiometric Fluorescent Probe.

Parkinson's disease (PD) represents the second most widespread neurodegenerative disease, and early monitoring and diagnosis are urgent at present. Tyrosine hydroxylase (TH) is a key enzyme for producing dopamine, the levels of which can serve as an indicator for assessing the severity and progression of PD. This renders the specific detection and visualization of TH a strategically vital way to meet the above demands. However, a fluorescent probe for TH monitoring is still missing. Herein, three rationally designed wash-free ratiometric fluorescent probes were proposed. Among them, TH-1 exhibited ideal photophysical properties and specific dual-channel bioimaging of TH activity in SH-SY5Y nerve cells. Moreover, the probe allowed for in vivo imaging of TH activity in zebrafish brain and living striatal slices of mice. Overall, the ratiometric fluorescent probe TH-1 could serve as a potential tool for real-time monitoring of PD in complex biosystems.

ROS-Responsive Bola-Lipid Nanoparticles as a Codelivery System for Gene/Photodynamic Combination Therapy.

The nonviral delivery systems that combine genes with photosensitizers for multimodal tumor gene/photodynamic therapy (PDT) have attracted much attention. In this study, a series of ROS-sensitive cationic bola-lipids were applied for the gene/photosensitizer codelivery. Zn-DPA was introduced as a cationic headgroup to enhance DNA binding, while the hydrophobic linking chains may facilitate the formation of lipid nanoparticles (LNP) and the encapsulation of photosensitizer Ce6. The length of the hydrophobic chain played an important role in the gene transfection process, and 14-TDZn containing the longest chains showed better DNA condensation, gene transfection, and cellular uptake. 14-TDZn LNPs could well load photosensitizer Ce6 to form 14-TDC without a loss of gene delivery efficiency. 14-TDC was used for codelivery of p53 and Ce6 to achieve enhanced therapeutic effects on the tumor cell proliferation inhibition and apoptosis. Results showed that the codelivery system was more effective in the inhibition of tumor cell proliferation than individual p53 or Ce6 monotherapy. Mechanism studies showed that the production of ROS after Ce6 irradiation could increase the accumulation of p53 protein in tumor cells, thereby promoting caspase-3 activation and inducing apoptosis, indicating some synergistic effect. These results demonstrated that 14-TDC may serve as a promising nanocarrier for gene/PDT combination therapy.

Cationic lipids from multi-component Passerini reaction for non-viral gene delivery: A structure-activity relationship study.

Although many types of cationic lipids have been developed as efficient gene vectors, the construction of lipid molecules with simple procedures remains challenging. Passerini reaction, as a classic multicomponent reaction, could directly give the α-acyloxycarboxamide products with biodegradable ester and amide bonds. Herein, two series of novel cationic lipids with heterocyclic pyrrolidine and piperidine as headgroups were synthesized through Passerini reaction (P-series) and amide condensation (A-series), and relevant structure-activity relationships on their gene delivery capability was studied. It was found that although both of the two series of lipids could form lipid nanoparticles (LNPs) which could effectively condense DNA, the LNP derived from P-series lipids showed higher transfection efficiency, serum tolerance, cellular uptake, and lower cytotoxicity. Unlike the A-series LNPs, the P-series LNPs showed quite different structure-activity relationship, in which the relative site of the secondary amine had significant effect on the transfection performance. The othro-isomers of the P-series lipids had lower cytotoxicity, but poor transfection efficiency, which was probably due to their unstable nature. Taken together, this study not only validated the feasibility of Passerini reaction for the construction of cationic lipids for gene delivery, but also afforded some clues for the rational design of effective non-viral lipidic gene vectors.

Molecular Engineering of Sulfone-Xanthone Chromophore for Enhanced Fluorescence Navigation.

Enriching the palette of high-performance fluorescent dyes is vital to support the frontier of biomedical imaging. Although various rhodamine skeletons remain the premier type of small-molecule fluorophores due to the apparent high brightness and flexible modifiability, they still suffer from the inherent defect of small Stokes shift due to the nonideal fluorescence imaging signal-to-background ratio. Especially, the rising class of fluorescent dyes, sulfone-substituted xanthone, exhibits great potential, but low chemical stability is also pointed out as the problem. Molecular engineering of sulfone-xanthone to obtain a large Stokes shift and high stability is highly desired, but it is still scarce. Herein, we present the combination modification method for optimizing the performance of sulfone-xanthone. These redesigned fluorescent skeletons owned greatly improved stability and Stokes shift compared with the parent sulfone-rhodamine. To the proof of bioimaging capacity, annexin protein-targeted peptide LS301 was introduced to the most promising dyes, J-S-ARh, to form the tumor-targeted fluorescent probe, J-S-LS301. The resulting probe, J-S-LS301, can be an outstanding fluorescence tool for the orthotopic transplantation tumor model of hepatocellular carcinoma imaging and on-site pathological analysis. In summary, the combination method could serve as a basis for rational optimization of sulfone-xanthone. Overall, the chemistry reported here broadens the scope of accessible sulfone-xanthone functionality and, in turn, enables to facilitate the translation of biomedical research toward the clinical domain.

A novel fluoropolymer as a protein delivery vector with robust adjuvant effect for cancer immunotherapy.

The inefficient treatment using protein-based nanovaccines is largely attributed to their inadequate immunogenicity. Herein, we developed a novel fluoropolymer (PF) via ring-opening polymerization and constructed a fluoropolymer-based nanovaccine for tumor immunotherapy. Due to the existence of fluoroalkyl chains, PF not only played a crucial role in tumor antigen delivery but also exhibited a remarkable adjuvant effect in enhancing the immunogenicity of nanovaccines. The nanovaccines formed by mixing PF with a model antigen ovalbumin (OVA) enhanced the uptake of antigen proteins by dendritic cells (DCs) and promoted the maturation and antigen presentation of DCs. Compared with free OVA, PF/OVA showed better efficacy in both pre-cancer prevention and tumor treatment. Furthermore, the proportion of CD4+ T and CD8+ T cells was significantly increased in lymph nodes and tumors of mice immunized with PF/OVA. Additionally, there was a great enhancement in the levels of key anti-tumor cytokines (TNF-α and IFN-γ) in the serum of the PF/OVA immunized mice. Our research has shown that fluoropolymer PF applied as a protein vector and adjuvant has great potential for the development of nanovaccines with robust immunogenicity.

Rational Design of pH-Independent and High-Fidelity Near-Infrared Tunable Fluorescent Probes for Tracking Leucine Aminopeptidase In Vivo.

Accurate detection of target analytes and generation of high-fidelity fluorescence signals are particularly critical in life sciences and clinical diagnostics. However, the majority of current NIR-I fluorescent probes are vulnerable to pH effects resulting in signal distortion. In this work, a series of fluorescence-tunable and pH-independent probes are reported by combining optically tunable groups of unsymmetric Si-rhodamines and introducing the methoxy instead of the spiro ring on the benzene ring at position 9. To validate the concept, the leucine aminopeptidase response site was introduced into Si-2,6OMe-NH2 with the best optical properties to synthesize Si-LAP for monitoring the intrahepatic LAP in vivo. Therefore, the design approach may provide a new and practical strategy for designing innovative functional fluorescent probes and generating high-stability and high-fidelity fluorescent signals.

A porphyrin-MOF-based integrated nanozyme system for catalytic cascades and light-enhanced synergistic amplification of cellular oxidative stress.

Peroxidase (POD)-like nanozymes have been found to act as nanoreactors for the generation of reactive oxygen species (ROS) to resolve drug resistance in the tumor microenvironment (TME). Amplifying cellular oxidative stress is considered to be a drug-free strategy to efficiently induce apoptosis in tumor cells. However, the limited content of intracellular hydrogen peroxide (H2O2) extremely restricts the performance of POD-like nanozymes to amplify cellular oxidative stress. Moreover, additional operational processes combined with exogenous reagents to achieve oxidative stress lead to a dilemma of extra cytotoxicity. Here, an integrated iron-porphyrin-MOF-based nanozyme composite named HA@GOx@PCN-224(Fe) (HGPF) was precisely designed and constructed. Generally, the POD-like nanozyme PCN-224(Fe) was used as a platform to immobilize glucose oxidase (GOx), and further embedded with hyaluronic acid (HA) to enable the targeting ability of tumor cells. When endocytosed by tumor cells, intracellular glucose was oxidized to H2O2 and gluconic acid catalyzed by immobilized GOx of HGPF. Afterwards, inspired by heme analogs, H2O2 was catalyzed by iron-porphyrin active sites of the HGPF nanozyme to generate hydroxyl radicals (˙OH). Under light irradiation, the iron-porphyrin of HGPF acted as a photosensitizer to facilely produce singlet oxygen (1O2). Such a synergistic generation of ROS strikingly amplified oxidative stress and induced severe apoptosis in tumor cells. HGPF was expected to integrate intracellular oxygen sources and overcome the dilemma of limited intracellular H2O2 content. Consequently, HGPF was constructed as an integrated nanoreactor to simultaneously achieve light-enhanced catalytic oxidation cascades, providing a promising strategy for a synergistic amplification of cellular oxidative stress.

A biocompatible polyethylene glycol/alginate composite hydrogel with significant reactive oxygen species consumption for promoting wound healing.

In areas of wound inflammation, excessive reactive oxygen species (ROS) may worsen the infection and lead to tissue damage, resulting in a vicious circle. Therefore, many hydrogels with sensitive ROS consumption capabilities and antibacterial properties have been widely developed and applied. These hydrogels usually achieve their ROS consumption capacity by introducing reactive active groups: however, these materials normally require complicated preparation procedures and have high potential toxicity. Inspired by these limitations, an integrated polyethylene glycol/alginate-based hydrogel (itg-PEGDA@SA) has been developed via a simple two-step process, where the inner PEGDA hydrogel (hdg-PEGDA) acts as a ROS scavenger and the outer sodium alginate hydrogel (SA) can be degraded to act as a recombinant human epidermal growth factor (rhEGF)-loaded platform to enhance the functionality of this composite hydrogel. Altogether, the itg-PEGDA@SA hydrogel showed significant ROS consumption and biocompatibility in vitro, and when applied for wound healing, the formation of uniform and ordered collagen fibers (stained using aniline blue) can be achieved. This hydrogel showed favorable attributes in ROS scavenging, and it can be a promising material for use in wound dressings and biomaterial fields.

Lipoic Acid-Based Poly(disulfide)s as Versatile Biomolecule Delivery Vectors and the Application in Tumor Immunotherapy.

Intracellular delivery of therapeutic biomacromolecules, including nucleic acids and proteins, attracts extensive attention in biotherapeutics for various diseases. Herein, a strategy is proposed for the construction of poly(disulfide)s for the efficient delivery of both nucleic acids and proteins into cells. A convenient photo-cross-linking polymerization was adopted between disulfide bonds in two modified lipoic acid monomers (Zn coordinated with dipicolylamine analogue (ZnDPA) and guanidine (GUA)). The disulfide-containing main chain of the resulting poly(disulfide)s was responsive to reducing circumstance, facilitating the release of cargos. By screening the feeding ratio of ZnDPA and GUA, the resulting poly(disulfide)s exhibited better performance in the delivery of nucleic acids including plasmid DNA and siRNA than commercially available transfection reagents. Cellular uptake results revealed that the polymer/cargo complexes entered the cells mainly following a thiol-mediated uptake pathway. Meanwhile, the polymer could also efficiently deliver proteins into cells without an obvious loss of protein activity, showing the versatility of the poly(disulfide)s for the delivery of various biomacromolecules. Moreover, the in vivo therapeutic effect of the materials was verified in the E.G7-OVA tumor-bearing mice. Ovalbumin-based nanovaccine induced a strong cellular immune response, especially cytotoxic T lymphocyte cellular immune response, and inhibited tumor growth. These results revealed the promise of the poly(disulfide)s in the application of both gene therapy and immunotherapy.

Daphnane-type diterpenoids from Stellera chamaejasme L. and their inhibitory activity against hepatocellular carcinoma cells.

Daphnane-type diterpenoids, which are scarce in nature, exhibit potent growth-inhibitory activities against various cancer cells. To identify more daphnane-type diterpenoids, the phytochemical components in the root extracts of Stellera chamaejasme L. were analysed in this study using the Global Natural Products Social platform and the MolNetEnhancer tool. Three undescribed 1α-alkyldaphnane-type diterpenoids (1-3; named stelleradaphnanes A-C) and 15 known analogues were isolated and characterised. The structures of these compounds were determined using ultraviolet and nuclear magnetic resonance spectroscopy. The stereo configurations of the compounds were determined using electronic circular dichroism. Next, the growth-inhibitory activities of isolated compounds against HepG2 and Hep3B cells were examined. Compound 3 exhibited potent growth-inhibitory activities against HepG2 and Hep3B cells with half-maximal inhibitory concentration values of 9.73 and 15.97 µM, respectively. Morphological and staining analyses suggested that compound 3 induced apoptosis in HepG2 and Hep3B cells.

Spleen-Targeted mRNA Delivery by Amphiphilic Carbon Dots for Tumor Immunotherapy.

In recent years, the application of mRNA vaccine-based tumor immunotherapy invigorated anti-tumor therapy. However, the low efficiency of mRNA delivery and the lack of targeting ability in vivo are the major obstacles to achieving highly efficient immunotherapy. In this work, we report a chemical library of amphiphilic carbon dots (ACDs) and the synthesized ACDs were applied to mRNA delivery, bio-imaging, and tumor immunotherapy. The ACDs can smoothly bind with mRNA to form ACDs@mRNA nanocomplexes, and the fluorescent properties of the ACDs afforded the nanoparticles with bio-imaging ability. By screening of the ACDs, O12-Tta-CDs were found to have optimal mRNA transfection efficiency and the ability of spleen-targeted delivery. In addition, O12-Tta-CDs can well transfect the immune cells and promote the maturation and antigen presentation of bone marrow-derived dendritic cells (BMDCs). Furthermore, O12-Tta-CDs@OVA-mRNA was successfully applied to inhibit tumor growth, and more specific T-cell infiltration was observed in spleen and tumors of mice after treatment in the E.G7-OVA tumor model. Besides, O12-Tta-CDs@OVA-mRNA also achieved a good therapeutic effect in tumor recurrence inhibition and tumor prophylactic experiments. This study provided a new direction for the design of mRNA vectors, which is promising in tumor immunotherapy.

Migration from Lysosome to Nucleus: Monitoring Lysosomal Alkalization-Related Biological Processes with an Aminofluorene-Based Probe.

Aberrant lysosomal alkalization is associated with various biological processes, such as oxidative stress, cell apoptosis, ferroptosis, etc. Herein, we developed a novel aminofluorene-based fluorescence probe named FAN to monitor the lysosomal alkalization-related biological processes by its migration from lysosome to nucleus. FAN possessed NIR emission, large Stokes shift, high pH stability, and high photostability, making it suitable for real-time and long-term bioimaging. As a lysosomotropic molecule, FAN can accumulate in lysosomes first and then migrate to the nucleus by right of its binding capability to DNA after lysosomal alkalization. In this manner, FAN was successfully used to monitor these physiological processes which triggered lysosomal alkalization in living cells, including oxidative stress, cell apoptosis, and ferroptosis. More importantly, at higher concentrations, FAN could also serve as a stable nucleus dye for the fluorescence imaging of the nucleus in living cells and tissues. This novel multifunctional fluorescence probe shows great promise for application in lysosomal alkalization-related visual research and nucleus imaging.

γ-Glutamyltranspeptidase and pH based "AND" logic gate fluorescent probe for orthotopic breast tumor imaging.

An "AND" logic gate-based NIR fluorescent probe Si-NH2-Glu was developed based on novel meso-amine Si-Rhodamine, which combined γ-glutamyl transpeptidase and pH dual-responsive sites. The features of Si-NH2-Glu enable it to be applied in orthotopic tumor imaging and fluorescence-guided surgery.

Fluorescent Self-Reporting Lipid Nanoparticles for Nitric Oxide/Gene Co-Delivery and Combination Therapy.

The combination cancer therapy of nitric oxide (NO) with gene therapy is a promising method for tumor treatment. However, efficient co-delivery of gas and therapeutic genes to tumor cells remains a challenge. Herein, we designed a nano-sized ultraviolet (UV) light-responsive cationic lipid vector DPNO(Zn). Fluorescence spectroscopy and confocal imaging experiments revealed that DPNO(Zn) lipid nanoparticles (LNPs) could rapidly release NO under low-power UV light irradiation. Moreover, the fluorescence turn-on might take place along with the release of NO, indicating the self-reporting ability. Gene delivery experiments showed that DPNO(Zn) LNPs had good gene transfection ability, making such materials a good candidate for gas/gene combination therapy. In vitro antitumor assay demonstrated that the co-delivery system was more effective in inhibiting tumor cell proliferation than individual NO or pTrail treatment. Studies on the mechanism of tumor cell apoptosis induced by NO/pTrail co-delivery showed that NO could not only effectively increase the accumulation of p53 protein in tumor cells, thereby promoting the activation of caspase-3, but also induce mitochondrial damage. On the other hand, the Trail protein expressed by pTrail gene could enhance the degree of NO-induced caspase-3 activation, indicating the synergistic effect. These results proved that DPNO(Zn) LNP may serve as a multifunctional nanocarrier for potential tumor therapy.

Rational Design of Polymethine Dyes with NIR-II Emission and High Photothermal Conversion Efficiency for Multimodal-Imaging-Guided Photo-Immunotherapy.

Phototheranostics have emerged and flourished as a promising pattern for cancer theranostics owing to their precise photoinduced diagnosis and therapeutic to meet the demands of precision medicine. The diagnosis information and therapeutic effect are directly determined by the fluorescence imaging ability and photothermal conversion efficiency (PCE) of phototheranostic agents. Hence, how to balance the competitive radiative and nonradiative processes of phototheranostic agents is the key factor to evaluate the phototheranostic effect. Herein, molecules named ICRs with high photostaibility  are rationally designed, exhibiting fluorescence emission in the second near-infrared window (NIR-II, 1000-1700 nm) and high PCE, which are related to the strong donor-acceptor (D-A) interaction and high reorganization energy Noteworthily, ICR-Qu with stronger D-A interaction and a large-sized conjugated unit encapsulated in nanoparticles exhibits high PCE (81.1%). In addition, ICR-QuNPs are used for fluorescence imaging (FLI), photoacoustic imaging (PAI), and photothermal imaging (PTI) to guide deep-tissue photonic hyperthermia, achieving precise removal and inhibition of breast cancer. Furthermore, combined with α-PD-1, ICR-QuNPs show huge potential to be a facile and efficient tool for photo-immunotherapy. More importantly, this study not only reports an "all-in-one" polymethine-based phototheranostic agent, but also sheds light on the exploration of versatile organic molecules for future practical applications.

Development of an Integrated System for Highly Selective Photoenzymatic Synthesis of Formic Acid from CO2.

Herein, a Zr-based dual-ligand MOFs with pre-installed Rh complex was employed for NADH regeneration in situ and also used for immobilization of formic acid dehydrogenase (FDH) in order to realize a highly efficient CO2 fixation system. Then, based on the detailed investigations into the photochemical and electrochemical properties, it is demonstrated that the introduction of the photosensitive meso-tetra(4-carboxyphenyl) porphin (TCPP) ligands increased the catalytic active sites and improved photoelectric properties. Furthermore, the electron mediator Rh complex, anchored on the zirconium-based dual-ligand MOFs, enhanced the efficiency of electron transfer efficiency and facilitated the separation of photogenerated electrons and holes. Compared with UiO-66-NH2 , Rh-H2 TCPP-UiO-66-NH2 exhibits an optimized valence band structure and significantly improved photocatalytic activity for NAD+ reduction, resulting the synthesis of formic acid from CO2 increased from 150 µg mL-1 (UiO-66-NH2 ) to 254 µg mL-1 (Rh-H2 TCPP-UiO-66-NH2 ). Moreover, the assembled photocatalyst-enzyme coupled system also allows facile recycling of expensive electron mediator, enzyme, and photocatalyst.

A chiral BINOL-based supramolecular gel enabling sensitive enantioselective and chemoselective collapse toward histidine.

A chiral small molecule gelator (R)-H3L based on 1,1'-bi-2,2'-naphthol (BINOL)-phosphoric acid was designed and prepared, which spontaneously forms a stable water-induced gel. The gelation mechanism was revealed by single crystal X-ray diffraction analysis and a number of spectroscopic methods. Addition of Cu2+ improved the gelation ability, and the resultant metal organic gel realized visual enantioselective and chemoselective recognition toward L-histidine from enantiomers of 19 amino acids via gel collapse. The gel showed a highly sensitive response to L-histidine, and as low as 0.01 equiv. of L-histidine relative to the critical gelation concentration of (R)-H3L-Cu caused the gel to collapse. This strategy of regulating the assembly behavior through the interaction of amino acids and metal ions not only provides a simple and direct way to distinguish enantiomers, but also provides insight into how metal ions regulate the organization of biological supramolecular systems.

Sodium Alginate-Doping Cationic Nanoparticle As Dual Gene Delivery System for Genetically Bimodal Therapy.

Photodynamic therapy occupies an important position in cancer therapy because of its minimal invasiveness and high spatiotemporal precision, and photodynamic/gene combined therapy is a promising strategy for additive therapeutic effects. However, the asynchronism and heterogeneity between traditional chemical photosensitizers and nucleic acid would restrict the feasibility of this strategy. KillerRed protein, as an endogenous photosensitizer, could be directly expressed and take effect in situ by transfecting KillerRed reporter genes into cells. Herein, a simple and easily prepared sodium alginate (SA)-doping cationic nanoparticle SA@GP/DNA was developed for dual gene delivery. The nanoparticles could be formed through electrostatic interaction among sodium alginate, polycation, and plasmid DNA. The title complex SA@GP/DNA showed good biocompatibility and gene transfection efficiency. Mechanism studies revealed that SA doping could facilitate the cellular uptake and DNA release. Furthermore, SA@GP/DNA was applied to the codelivery of p53 and KillerRed reporter genes for the synergistic effect combining p53-mediated apoptosis therapy and KillerRed-mediated photodynamic therapy. The ROS generation, tumor cell growth inhibition, and apoptosis assays proved that the dual-gene transfection could mediate the better effect compared with single therapy. This rationally designed dual gene codelivery nanoparticle provides an effective and promising platform for genetically bimodal therapy.