Core–Shell Bi2Se3@mSiO2‐PEG as a Multifunctional Drug‐Delivery Nanoplatform for Synergistic Thermo‐Chemotherapy with Infrared Thermal Imaging of Cancer Cells

Thermo‐chemotherapy combining photothermal therapy (PTT) with chemotherapy has become a potent approach for antitumor treatment. In this study, a multifunctional drug‐delivery nanoplatform based on polyethylene glycol (PEG)‐modified mesoporous silica‐coated bismuth selenide nanoparticles (referred to as Bi₂Se₃@mSiO₂‐PEG NPs) is developed for synergistic PTT and chemotherapy with infrared thermal (IRT) imaging of cancer cells. The product shows no/low cytotoxicity, strong near‐infrared (NIR) optical absorption, high photothermal conversion capacity, and stability. Utilizing the prominent photothermal effect, high‐contrast IRT imaging and efficient photothermal killing effect on cancer cells are achieved upon NIR laser irradiation. Moreover, the successful mesoporous silica coating of the Bi₂Se₃@mSiO₂‐PEG NPs cannot only largely improve the stability but also endow the NPs high drug loading capacity. As a proof‐of‐concept model, doxorubicin (DOX) is successfully loaded into the NPs with rather high loading capacity (≈50.0%) via the nanoprecipitation method. It is found that the DOX‐loaded NPs exhibit a bimodal on‐demand pH‐ and NIR‐responsive drug release property, and can realize effective intracellular drug delivery for chemotherapy. The synergistic thermo‐chemotherapy results in a significantly higher antitumor efficacy than either PTT or chemotherapy alone. The work reveals the great potential of such core–shell NPs as a multifunctional drug‐delivery nanosystem for thermo‐chemotherapy.     

Control of Surface Ligand Density on PEGylated Gold Nanoparticles for Optimized Cancer Cell Uptake

Surface chemistry plays a critical role in the solution phase behavior of gold nanoparticles (Au NPs) for applications such as in situ diagnostics and drug delivery. Polyethylene glycol (PEG), a hydrophilic polymer with low immunogenicity, is most commonly used for protecting Au NPs for biomedical applications. The ligand density and molecular weight of PEG on the gold nanoparticle surface are key factors that control the particles’ behavior. Specifically, the total density of PEG ligands gives rise to a transition from a disorganized, deformable polymer “mushroom” orientation to a more rigid “brush” orientation. Here, it is investigated how to rationally control this transition for Au NPs coated with PEG‐SH molecules within the weight range of 0.55 to 5 kDa, and evaluate their subsequent interaction with cancer cells. Several complementary methods are used to evaluate the effect of PEGylation on biologically relevant aspects, including surface ligand density, hydrodynamic size, dispersity, and cellular toxicity. In this work, the optimal synthesis ratios of PEG:Au NPs for achieving stability and maximum dispersity with 0.55, 1, 2, and 5 kDa PEG are determined to be 2500, 700, 500, and 300, respectively. Importantly, ratios that exceed those necessary for maximum dispersion of the Au NPs as determined by UV–vis and DLS are found to be the best ratios for highest cell viability.     

Facile Synthesis of Lactobionic Acid‐Targeted Iron Oxide Nanoparticles with Ultrahigh Relaxivity for Targeted MR Imaging of an Orthotopic Model of Human Hepatocellular Carcinoma

Development of multifunctional nanoprobes for tumor diagnosis is extremely important in the field of molecular imaging. In this study, the facile synthesis of lactobionic acid (LA)‐targeted superparamagnetic iron oxide (Fe₃O₄) nanoparticles (NPs) with ultrahigh relaxivity for targeted magnetic resonance (MR) imaging of an orthotopic hepatocellular carcinoma (HCC) is reported. Polyethyleneimine (PEI)‐stabilized Fe₃O₄ NPs prepared via a mild reduction route are sequentially coupled with fluorescein isothiocyanate and polyethylene glycol‐LA (LA‐PEG‐COOH) segment, followed by acetylation of the remaining PEI surface amines. The formed LA‐targeted Fe₃O₄ NPs are thoroughly characterized. It is shown that the developed multifunctional LA‐targeted Fe₃O₄ NPs are colloidally stable and water‐dispersible, display an ultrahigh r ₂ relaxivity (579.89 × 10^?3 m ^?1 s^?1) and excellent hemocompatibility and cytocompatibility in the given concentration range, and can target HepG2 cells overexpressing asialoglycoprotein receptors as confirmed by in vitro cellular uptake assay, flow cytometry, and confocal microscopy. Most strikingly, the developed multifunctional LA‐targeted Fe₃O₄ NPs can be used as a nanoprobe for targeted MR imaging of HepG2 cells in vitro and an orthotopic tumor model of HCC in vivo. With the ultrahigh r ₂ relaxivity and the versatile PEI amine‐mediated conjugation chemistry, a range of different Fe₃O₄ NP‐based nanoprobes may be developed for theranostics of different types of cancer.     

PEGylated polyethylenimine-stabilized polypyrrole nanoparticles loaded with DOX for chemo-photothermal therapy of cancer cells

Combination of kinds of therapy modalities is promising for effective cancer treatment. Herein, a kind of multifunctional nanoparticles (NPs) was developed for cancer chemo-photothermal therapy applications. Polypyrrole (PPy) NPs were formed using a facile polymerization method using poly(ethyleneimine) (PEI) as stabilizer, followed by polyethylene glycol (PEG) modification and anticancer drug doxorubicin (DOX) loading. Showing obvious absorbance in the NIR range, the obtained PPy-PEI-PEG NPs displayed well photothermal ability with desirable photothermal stability. The release of the loaded DOX can be promoted by pH and laser stimulation. Compared with single therapy modality, the combination of chemotherapy and photothermal therapy showed higher cancer cell killing effect. The cellular internalization of the obtained NPs was proved to be effective. The developed multifunctional NPs are promising candidates for combined therapy of cancer cells.     

Taxanes Hybrid Nanovectors: From Design to Physico‐Chemical Evaluation of Docetaxel and Paclitaxel Gold (III)‐PEGylated Complex Nanocarriers

This study gives an original methodology to synthetize novel metallo‐drugs nanoparticles relevant for medicinal chemistry. Gold (HAuCl₄) are complexes with antitumor compounds (paclitaxel (PTX); docetaxel (DTX)) and dicarboxylic acid‐terminated polyethylene‐glycol (PEG) that plays a role of surfactants. The proposed synthesis is fast and leads to hybrid‐metal nanoparticles (AuNPs) in which drug solubility is improved. The interactions between drugs (DTX, PTX), PEG diacid (PEG), and Au (III) ions to form hybrid nanocarriers called DTX IN PEG‐AuNPs and PTX IN PEG‐AuNPs, are characterized by various analytical techniques (Raman and UV–vis spectroscopies) and transmission electron microscopy. The efficient drugs release under pH conditions is also achieved and characterized showing an amazing reversible equilibrium between Au (III)‐complex‐drug and Au⁰NPs. For therapeutic purposes, such AuNPs are then decorated with the anti‐EGFR polyclonal antibodies, which specifically recognizes the hERG1 channel aberrantly expressed on the membrane of human lung cancer cells. This paper, through an original chemical approach, will occupy an important position in the field of nanomedicine, and hope that novel perspectives will be proposed for the development of high drug‐loading nanomedicines.     

The Cellular Interactions of PEGylated Gold Nanoparticles: Effect of PEGylation on Cellular Uptake and Cytotoxicity

Poly(ethylene glycol) (PEG) is frequently used to coat various medical nanoparticles (NPs). As PEG is known to minimize NP interactions with biological specimens, the question remains whether PEGylated NPs are intrinsically less toxic or whether this is caused by reduced NP uptake. In the present work, the effect of gold NP PEGylation on uptake by three cell types is compared and evaluated the effect on cell viability, oxidative stress, cell morphology, and functionality using a multiparametric methodology. The data reveal that PEGylation affects cellular NP uptake in a cell‐type‐dependent manner and influences toxicity by different mechanisms. At similar intracellular NP numbers, PEGylated NPs are found to yield higher levels of cell death, mostly by induction of oxidative stress. These findings reveal that PEGylation significantly reduces NP uptake, but that at similar functional (= cell‐associated) NP levels, non‐PEGylated NPs are better tolerated by the cells.     

Controlled Self‐Assembly of Mesoporous CuO Networks Guided by Organic Interlinking

The controlled aggregation of copper oxide nanoparticles (CuO NPs) induced by a multitopic carboxylic acid allows the formation of mesoporous structures with high surface area, in the order of 100 m² g^?1, as demonstrated herein. The main novelty in the designed process is the use, as a previous step, of a sacrificeable monotopic carboxylate ligand for capping the CuO NPs. This step avoids the often observed unwanted behavior of uncontrolled aggregation and material densification. The monotopic 3,6,9‐trioxadecanoate (HTODA) is used as the capping agent to prepare TODA@CuO, a starting material that forms colloidal dispersions in ethanol. For NPs self‐assembly, the bulky tricarboxylic acid 4,4′,4′′,‐benzene‐1,3,5‐triyl‐tris(benzoic acid) (H₃BTB) is chosen as an efficient interlinker in the controlled aggregation. The obtained mesoporous network shows a considerable thermal stability, retaining ≈70% of its specific surface area after annealing at 300 °C under vacuum. Thermal treatment involves TODA capping agent elimination, but not BTB linker. The simultaneous reduction of the CuO NPs to a Cu₂O/Cu mixture is observed.     

Self‐Assemble Polymeric Nanoparticle with GSH Exhaustion for SPECT Imaging–Guided Enhanced Radioisotope Therapy

Exploiting biocompatible nanomaterials for cancer theranostics has attracted great attention in recent years. Herein, a multifunctional self‐assembled nanoparticle based on a biocompatible polymer that contains 3‐(4‐hydroxyphenyl) propionic acid N‐hydroxysuccinimide ester (HOPA) for radiolabeling and piperlongumine (PL) for exhausting endogenous glutathione (GSH) (HOPA‐C18PMH‐PEG/PL) is successfully synthesized. With radionuclide ¹²⁵I labeling, SPECT imaging shows high tumor uptake of HOPA‐C18PMH‐PEG/PL after intravenous injection. The in vitro and in vivo combined radioisotope therapy (RIT) and chemotherapy using ¹³¹I‐labeled HOPA‐C18PMH‐PEG/PL is then carried out, achieving synergistic antitumor effect. This is because the reactive oxygen species (ROS) level in the tumor sites of mice treated with ¹³¹I‐labeled HOPA‐C18PMH‐PEG/PL is increased after the exhaustion of GSH by PL. Additionally, such a strategy (exhausting GSH and increasing ROS) induces no obvious toxicity to normal tissue. Therefore, as‐made polymeric nanoparticles exhibit multifunctional properties for SPECT imaging–guided combined RIT and chemotherapy in one system. This finding will further promote polymeric nanoparticle–based RIT of cancer and is expected to be used for future clinical transformation.     

In Vitro Evaluation of Non‐Protein Adsorbing Breast Cancer Theranostics Based on 19F‐Polymer Containing Nanoparticles

Eight fluorinated nanoparticles (NPs) are synthesized, loaded with doxorubicin (DOX), and evaluated as theranostic delivery platforms to breast cancer cells. The multifunctional NPs are formed by self‐assembly of either linear or star‐shaped amphiphilic block copolymers, with fluorinated segments incorporated in the hydrophilic corona of the carrier. The sizes of the NPs confirm that small circular NPs are formed. The release kinetics data of the particles reveals clear hydrophobic core dependence, with longer sustained release from particles with larger hydrophobic cores, suggesting that the DOX release from these carriers can be tailored. Viability assays and flow cytometry evaluation of the ratios of apoptosis/necrosis indicate that the materials are non‐toxic to breast cancer cells before DOX loading; however, they are very efficient, similar to free DOX, at killing cancer cells after drug encapsulation. Both flow cytometry and confocal microscopy confirm the cellular uptake of NPs and DOX‐NPs into breast cancer cells, and in vitro ¹⁹F‐MRI measurement shows that the fluorinated NPs have strong imaging signals, qualifying them as a potential in vivo contrast agent for ¹⁹F‐MRI.     

Importance of poly(ethylene glycol) conformation for the synthesis of silver nanoparticles in aqueous solution

Silver nanoparticles (NPs) were prepared using silver nitrate (AgNO₃) as a precursor in an aqueous solution of poly(ethylene glycol) (PEG), which acted as both a reducing and stabilizing agent. The UV/Vis spectra showed that PEG 100 (100 kg/mol) has a remarkable capability to produce silver NPs at 80 °C, but the production of silver NPs by both PEG 2 (2 kg/mol) and PEG 35 (35 kg/mol) was negligible. This difference was explained by the conformation of PEG in the reaction solution: the entangled conformation for PEG 100 and the single-coiled conformation for PEG 2 and PEG 35, which were confirmed by pulse-field-gradient ¹H NMR and viscosity measurements. In an aqueous solution, the entangled conformation of PEG 100 facilitated the reduction reaction by caging silver ions and effectively prevented the agglomeration of formed NPs. The reaction in an aqueous PEG 100 solution was observed to be stable under the conditions of a prolonged reaction time or an increased temperature, while no reduction reaction occurred in the PEG 2 solution. The synthesis of silver NPs by PEG 100 was well controlled to produce fine silver NPs with 3.68 ± 1.03 nm in diameter, the size of which remained relatively constant throughout the reaction.     

Dye‐Sensitized Core/Shell Upconversion Nanoparticles for Detecting Nitrites in Plant Cells

A fluorescent nanoprobe is reported for rapid detection of nitrites (NO₂^?) in plant cells. The probe is fabricated by linking neutral reds (NR) to the surface of upconversion fluorescent core/shell nanocrystalline with the bridging of polyethylene glycol (PEG) molecules. The fluorescence of upconversion nanoparticles (UCNPs) is stored by NR through fluorescence resonance energy transfer (FRET) under 980 nm excitation that can be released by further linking to NO₂^?. It is observed that the intensity rate of green to red emission of NR‐modified UCNPs changes linearly with increasing the amount of NO₂^?. So that concentration of NO₂^? can be accordingly addressed. Worth mentioning is that, comparing with bare core upconversion nanoparticles (NPs), core/shell UCNPs can greatly reduce the surface quenching of the fluorescence induced by solvents instead of NR and thus leading to the enhancement of signal‐to‐noise ratios. Moreover, excitation of core/shell UCNPs requires only a much lower power (0.06 W cm^?2) than bare cores which is beneficial to reducing the decomposition of NR to stabilize the FRET processes. Under the optimum conditions, the detection limit of nitrite in plant cells was 0.1 µg mL^?1.     

Synergistic Effect of Thermo‐Radiotherapy Using Au@FeS Core–Shell Nanoparticles as Multifunctional Therapeutic Nanoagents

Imaging guided combined therapy has attracted great attention in recent years. This study develops core–shell Au@FeS nanoparticles with polyethylene glycol (PEG) coating as multifunctional nanotheranostic agent for tumor imaging and combined photothermal therapy (PTT) and radiotherapy (RT). In this Au@FeS nanostructure, the gold core can act as a radiosensitizer for enhanced RT, while FeS shell offers contrast for T2‐weighted magnetic resonance imaging and endows the nanoparticles with strong high near‐infrared (NIR) for photoacoustic imaging and PTT. As demonstrated by both in vitro and in vivo experiments, Au@FeS‐PEG can act as excellent therapeutic agent for cancer synergistic treatment. More importantly, mild PTT boosts the blood flow into tumor and increases oxygenation to overcome the tumor hypoxia microenvironment, further enhancing the efficacy of RT. Moreover, Au@FeS‐PEG induces on obvious toxicity at a high dose (20 mg kg^?1) to the treated mice as evidenced by blood biochemistry. Therefore, this study brings an excellent strategy for cancer enhanced RT through NIR‐triggered mild PTT to overcome hypoxia‐associated radioresistance.     

Structure and Stability of PEG‐ and Mixed PEG‐Layer‐Coated Nanoparticles at High Particle Concentrations Studied In Situ by Small‐Angle X‐Ray Scattering

Ligand‐layer structure and stability of gold nanoparticles (AuNP) coated with α‐methoxypoly(ethylene glycol)‐ω‐(11‐mercaptoundecanoate) (PEGMUA) layers and mixed layers of PEGMUA and 11‐mercaptoundecanoic acid (MUA) at high AuNP concentrations are studied in situ by small‐angle X‐ray scattering (SAXS). The thickness of the ligand layer is modified by the molecular weight of the PEG‐ligands (2 and 5 kDa), and the PEG‐grafting density is decreased by coadsorption of MUA. The response of the conjugates to a pressure of up to 4 kbar is probed. The results indicate strongly hydrated PEG layers at high grafting densities. The stability of the mixed ligand‐layer conjugates is lower. This is most probably due to enhanced interparticle PEG–PEG interactions at lower grafting densities. The presented study demonstrates that a detailed structural characterization of polymer ligand layers in situ and in response to external stimuli is possible with SAXS.     

Polydopamine Nanoparticle as a Multifunctional Nanocarrier for Combined Radiophotodynamic Therapy of Cancer

Combination of different therapeutic strategies to treat cancer has attracted tremendous attention in recent years. Herein, the authors develop polydopamine (PDA) nanoparticles with polyethylene glycol (PEG) modification as a multifunctional nanocarrier for coloading photosensitizer chlorine6 (Ce6) and curcumin (Cur) for combined photodynamic therapy (PDT) and radiotherapy (RT) of cancer. PEGylated PDA nanoparticles (PDA‐PEG) exhibit well water soluble and biocompatible in different physiological solutions and cause no obvious toxicity to cancer cells. In this nanoparticle, the loaded Ce6 can trigger the generation of single oxygen under near‐infrared laser irradiation for PDT, while the loaded Cur can act as an excellent radiosensitizer under X‐ray irradiation for enhanced external RT. As demonstrated by in vitro and in vivo therapeutic efficiency, combined PDT and RT based on PDA‐PEG/Cur/Ce6 nanoparticles exhibits significant inhibition the growth of cancer cells, revealing perfect performance in cancer treatment. Therefore, the study not only presents a polymer‐based theranostic platform for cancer treatment but also demonstrates the potential applications of combined RT and PDT for the future clinic cancer therapy.     

Selective Targeting of Lymphoma Cells by Monoclonal Antibody Grafted onto Zwitterionic-Functionalized Nanoparticles

Nanomedicine is considered a promising alternative to improve cancer diagnosis and treatment. Particularly, the use of nanoparticles (NPs) has enabled the encapsulation of highly toxic anticancer drugs, facilitated ultimate targeting, and allowed tailoring of drug delivery. However, when in biological fluids, these NPs are coated by proteins which hide the targeting moieties and suppress the engineered biological outcome. Herein, how the Ki-1 monoclonal antibody (mAb) can preserve its targetability through grafting on the surface of zwitterionic-functionalized nanoparticles, is unveiled. Zwitterions, known for their stealth ability, are used to minimize unspecific NPs protein adsorption and consequently maintain mAb functionality. In this work, Ki-1 mAb is used as it recognizes TNFRSF8 (CD30⁺) transmembrane protein overexpressed on CD30⁺ lymphoma cells such as L540 cells. While nonfunctionalized NPs show negligible toxic effects toward L540 cells, the Ki-1-functionalized structure demonstrates cytotoxicity, since they undergo cellular uptake, suggesting a receptor-mediated internalization. This dual-functionalization strategy provides a promising multifunctional nanoplatform toward future personalized medicine applications, minimizing unspecific protein adsorption on NPs and ensuring selective cancer cell targeting.     

The Toxicity of Silver Nanoparticles Depends on Their Uptake by Cells and Thus on Their Surface Chemistry

A set of three types of silver nanoparticles (Ag NPs) are prepared, which have the same Ag cores, but different surface chemistry. Ag cores are stabilized with mercaptoundecanoic acid (MUA) or with a polymer shell [poly(isobutylene‐alt‐maleic anhydride) (PMA)]. In order to reduce cellular uptake, the polymer‐coated Ag NPs are additionally modified with polyethylene glycol (PEG). Corrosion (oxidation) of the NPs is quantified and their colloidal stability is investigated. MUA‐coated NPs have a much lower colloidal stability than PMA‐coated NPs and are largely agglomerated. All Ag NPs corrode faster in an acidic environment and thus more Ag(I) ions are released inside endosomal/lysosomal compartments. PMA coating does not reduce leaching of Ag(I) ions compared with MUA coating. PEGylation reduces NP cellular uptake and also the toxicity. PMA‐coated NPs have reduced toxicity compared with MUA‐coated NPs. All studied Ag NPs were less toxic than free Ag(I) ions. All in all, the cytotoxicity of Ag NPs is correlated on their uptake by cells and agglomeration behavior.     

Chiral Noble Metal Nanoparticles and Nanostructures

The origins of chirality and chiroptical properties in ligand‐protected gold and silver nanoparticles (NPs) are considered herein. Current conceptual models including the chiral core model, dissymmetric field model, and chiral footprint model are described as mechanisms that contribute to the understanding of chirality in these systems. Then, recent studies on thiolate‐stabilized gold NPs, phosphine‐stabilized gold NPs, multi‐ligand‐stabilized silver NPs, and DNA‐stabilized silver NPs are discussed. Insights into the origin of chiroptical properties including reasons for large Cotton effects in circular dichroism spectra are considered using both experimental and theoretical data available. Theoretical calculations using density functional theory (DFT) and time‐dependent DFT methods are found to be extremely useful for providing insights into the origin of chirality. The origin of chirality in ligand‐protected gold and silver NPs can be considered to be a complex phenomenon, arising from a combination of the three conceptual models.     

Safety Issue of Changed Nanotoxicity of Zinc Oxide Nanoparticles in the Multicomponent System

When nanomaterials are exposed to complex systems, such as food, they may cause significant changes in physical and chemical properties and even toxicity. The toxicity evaluation of complex systems is urgent. Unfortunately, so far, there is no database established about the toxicity changes of nanoparticles in composite systems. In this paper, the changes and toxicity mechanism of zinc oxide nanoparticles (ZnO NPs) in a composite system are studied. The results show that the dissolution of zinc ions (Zn²⁺) in acidic systems (vitamin C, tartaric acid, or citric acid) increases the toxicity of ZnO NPs. However, the toxicity of ZnO NPs is reduced by the complexation effect with Zn²⁺ in phosphoric acid, phosphate, and glutathione systems. The influence of titanium dioxide nanoparticles (TiO₂ NPs) on the toxicity of ZnO NPs depends on size and surface properties. In brief, the intracellular Zn²⁺ homeostasis level is the decisive factor in determining the toxicity change in complex systems. The results indicate that the toxicity changes are very different in combined systems, which may have potential food safety issues, especially for unstable nanoparticles.     

Facile Synthesis of Gd(OH)3‐Doped Fe3O4 Nanoparticles for Dual‐Mode T1‐ and T2‐Weighted Magnetic Resonance Imaging Applications

The facile hydrothermal synthesis of polyethyleneimine (PEI)‐coated iron oxide (Fe₃O₄) nanoparticles (NPs) doped with Gd(OH)₃ (Fe₃O₄‐Gd(OH)₃‐PEI NPs) for dual mode T₁‐ and T₂‐weighted magnetic resonance (MR) imaging applications is reported. In this approach, Fe₃O₄‐Gd(OH)₃‐PEI NPs are synthesized via a hydrothermal method in the presence of branched PEI and Gd(III) ions. The PEI coating onto the particle surfaces enables further modification of poly(ethylene glycol) (PEG) in order to render the particles with good water dispersibility and improved biocompatibility. The formed Fe₃O₄‐Gd(OH)₃‐PEI‐PEG NPs have a Gd/Fe molar ratio of 0.25:1 and a mean particle size of 14.4 nm and display a relatively high r₂ (151.37 × 10^?3m ^?1 s^?1) and r₁ (5.63 × 10^?3m ^?1 s^?1) relaxivity, affording their uses as a unique contrast agent for T₁‐ and T₂‐weighted MR imaging of rat livers after mesenteric vein injection of the particles and the mouse liver after intravenous injection of the particles, respectively. The developed Fe₃O₄‐Gd(OH)₃‐PEI‐PEG NPs may hold great promise to be used as a contrast agent for dual mode T₁‐ and T₂‐weighted self‐confirmation MR imaging of different biological systems.     

Surface‐enhanced Raman scattering of molecules adsorbed on Co‐doped ZnO nanoparticles

Transition‐metal‐doped semiconductor nanoparticles (NPs) have been well studied for their optical and catalytic properties but seldom studied by surface‐enhanced Raman scattering (SERS). In this paper, transition‐metal‐doped semiconductor NPs are investigated for their SERS property. Four groups of Co‐doped (0.5, 1, 3, and 5%) ZnO (Co ZnO) NPs and pure ZnO NPs were synthesized and studied. When 4‐mercaptobenzoic acid was used as probing molecule, significant SERS signals were obtained on all the five samples. Moreover, it is very interesting to observe a relationship between the Co‐doping concentration and enhancement of the SERS signals. SERS intensities first increase with doping concentration (up to 1%), and then decrease with further increase in doping concentration (up to 5%). Charge transfer (CT) is considered to be the main contribution to this phenomenon. Different CT ratios from substrates to molecules seem to induce different intensities of the SERS signals. In our experiments, the crystalline defects of Co ZnO NPs caused by the Co dopant affect the CT ratios. A possible mechanism of CT from the valance band of Co ZnO NPs to the lower unoccupied molecular orbital of the molecules via energy of the surface states is suggested. X‐ray photoelectron spectra, UV vis spectra, and Raman spectra were used to characterize the structure and defects in Co ZnO NPs. Copyright © 2011 John Wiley & Sons, Ltd.