Nanoparticle-Based Follistatin Messenger RNA Therapy for Reprogramming Metastatic Ovarian Cancer and Ameliorating Cancer-Associated Cachexia.

This study presents the first messenger RNA (mRNA) therapy for metastatic ovarian cancer and cachexia-induced muscle wasting based on lipid nanoparticles that deliver follistatin (FST) mRNA predominantly to cancer clusters following intraperitoneal administration. The secreted FST protein, endogenously synthesized from delivered mRNA, efficiently reduces elevated activin A levels associated with aggressive ovarian cancer and associated cachexia. By altering the cancer cell phenotype, mRNA treatment prevents malignant ascites, delays cancer progression, induces the formation of solid tumors, and preserves muscle mass in cancer-bearing mice by inhibiting negative regulators of muscle mass. Finally, mRNA therapy provides synergistic effects in combination with cisplatin, increasing the survival of mice and counteracting muscle atrophy induced by chemotherapy and cancer-associated cachexia. The treated mice develop few nonadherent tumors that are easily resected from the peritoneum. Clinically, this nanomedicine-based mRNA therapy can facilitate complete cytoreduction, target resistance, improve resilience during aggressive chemotherapy, and improve survival in advanced ovarian cancer.

Transarterial Delivery of a Biodegradable Single-Agent Theranostic Nanoprobe for Liver Tumor Imaging and Combinatorial Phototherapy.

PURPOSE: To assess selective accumulation of biodegradable nanoparticles within hepatic tumors after transarterial delivery for in vivo localization and combinatorial phototherapy. MATERIALS AND METHODS: A VX2 hepatic tumor model was used in New Zealand white rabbits. Transarterial delivery of silicon naphthalocyanine biodegradable nanoparticles was performed using a microcatheter via the proper hepatic artery. Tumors were exposed via laparotomy, and nanoparticles were observed by near-infrared (NIR) fluorescence imaging. For phototherapy, a handheld NIR laser (785 nm) at 0.6 W/cm2 was used to expose tumor or background liver, and tissue temperatures were assessed with a fiberoptic temperature probe. Intratumoral reactive oxygen species formation was assessed using a fluorophore (2',7'-dichlorodihydrofluorescein diacetate). RESULTS: Nanoparticles selectively accumulated within viable tumor by NIR fluorescence. Necrotic portions of tumor did not accumulate nanoparticles, consistent with a vascular distribution. NIR-dependent heat generation was observed with nanoparticle-containing tumors, but not in background liver. No heat was generated in the absence of NIR laser light. Reactive oxygen species were formed in nanoparticle-containing tumors exposed to NIR laser light, but not in background liver treated with NIR laser or in tumors in the absence of NIR light. CONCLUSIONS: Biodegradable nanoparticle delivery to liver tumors from a transarterial approach enabled selective in vivo tumor imaging and combinatorial phototherapy.

Biocompatible Nanoclusters with High Heating Efficiency for Systemically Delivered Magnetic Hyperthermia.

Despite its promising therapeutic potential, nanoparticle-mediated magnetic hyperthermia is currently limited to the treatment of localized and relatively accessible cancer tumors because the required therapeutic temperatures above 40 °C can only be achieved by direct intratumoral injection of conventional iron oxide nanoparticles. To realize the true potential of magnetic hyperthermia for cancer treatment, there is an unmet need for nanoparticles with high heating capacity that can efficiently accumulate at tumor sites following systemic administration and generate desirable intratumoral temperatures upon exposure to an alternating magnetic field (AMF). Although there have been many attempts to develop the desired nanoparticles, reported animal studies reveal the challenges associated with reaching therapeutically relevant intratumoral temperatures following systemic administration at clinically relevant doses. Therefore, we developed efficient magnetic nanoclusters with enhanced heating efficiency for systemically delivered magnetic hyperthermia that are composed of cobalt- and manganese-doped, hexagon-shaped iron oxide nanoparticles (CoMn-IONP) encapsulated in biocompatible PEG-PCL (poly(ethylene glycol)- b-poly(ε-caprolactone))-based nanocarriers. Animal studies validated that the developed nanoclusters are nontoxic, efficiently accumulate in ovarian cancer tumors following a single intravenous injection, and elevate intratumoral temperature up to 44 °C upon exposure to safe and tolerable AMF. Moreover, the obtained results confirmed the efficiency of the nanoclusters to generate the required intratumoral temperature after repeated injections and demonstrated that nanocluster-mediated magnetic hyperthermia significantly inhibits cancer growth. In summary, this nanoplatform is a milestone in the development of systemically delivered magnetic hyperthermia for the treatment of cancer tumors that are difficult to access for intratumoral injection.

Increasing lean muscle mass in mice via nanoparticle-mediated hepatic delivery of follistatin mRNA.

Muscle atrophy occurs during chronic diseases, resulting in diminished quality of life and compromised treatment outcomes. There is a high demand for therapeutics that increase muscle mass while abrogating the need for special dietary and exercise requirements. Therefore, we developed an efficient nanomedicine approach capable of increasing muscle mass. Methods: The therapy is based on nanoparticle-mediated delivery of follistatin messenger RNA (mRNA) to the liver after subcutaneous administration. The delivered mRNA directs hepatic cellular machinery to produce follistatin, a glycoprotein that increases lean mass through inhibition of negative regulators of muscle mass (myostatin and activin A). These factors are elevated in numerous disease states, thereby providing a target for therapeutic intervention. Results: Animal studies validated that mRNA-loaded nanoparticles enter systemic circulation following subcutaneous injection, accumulate and internalize in the liver, where the mRNA is translated into follistatin. Follistatin serum levels were elevated for 72 h post injection and efficiently reduced activin A and myostatin serum concentrations. After eight weeks of repeated injections, the lean mass of mice in the treatment group was ~10% higher when compared to that of the controls. Conclusion: Based on the obtained results demonstrating an increased muscle mass as well as restricted fat accumulation, this nanoplatform might be a milestone in the development of mRNA technologies and the treatment of muscle wasting disorders.

Intraperitoneal nanotherapy for metastatic ovarian cancer based on siRNA-mediated suppression of DJ-1 protein combined with a low dose of cisplatin.

Herein, we report an efficient combinatorial therapy for metastatic ovarian cancer based on siRNA-mediated suppression of DJ-1 protein combined with a low dose of cisplatin. DJ-1 protein modulates, either directly or indirectly, different oncogenic pathways that support and promote survival, growth, and invasion of ovarian cancer cells. To evaluate the potential of this novel therapy, we have engineered a cancer-targeted nanoplatform and validated that DJ-1 siRNA delivered by this nanoplatform after intraperitoneal injection efficiently downregulates the DJ-1 protein in metastatic ovarian cancer tumors and ascites. In vivo experiments revealed that DJ-1 siRNA monotherapy outperformed cisplatin alone by inhibiting tumor growth and increasing survival of mice with metastatic ovarian cancer. Finally, three cycles of siRNA-mediated DJ-1 therapy in combination with a low dose of cisplatin completely eradicated ovarian cancer tumors from the mice, and there was no cancer recurrence detected for the duration of the study, which lasted 35 weeks.

A Tumor-Activatable Theranostic Nanomedicine Platform for NIR Fluorescence-Guided Surgery and Combinatorial Phototherapy.

Fluorescence image-guided surgery combined with intraoperative therapeutic modalities has great potential for intraoperative detection of oncologic targets and eradication of unresectable cancer residues. Therefore, we have developed an activatable theranostic nanoplatform that can be used concurrently for two purposes: (1) tumor delineation with real-time near infrared (NIR) fluorescence signal during surgery, and (2) intraoperative targeted treatment to further eliminate unresected disease sites by non-toxic phototherapy. Methods: The developed nanoplatform is based on a single agent, silicon naphthalocyanine (SiNc), encapsulated in biodegradable PEG-PCL (poly (ethylene glycol)-b-poly(ɛ-caprolactone)) nanoparticles. It is engineered to be non-fluorescent initially via dense SiNc packing within the nanoparticle's hydrophobic core, with NIR fluorescence activation after accumulation at the tumor site. The activatable nanoplatform was evaluated in vitro and in two different murine cancer models, including an ovarian intraperitoneal metastasis-mimicking model. Furthermore, fluorescence image-guided surgery mediated by this nanoplatform was performed on the employed animal models using a Fluobeam® 800 imaging system. Finally, the phototherapeutic efficacy of the developed nanoplatform was demonstrated in vivo. Results: Our in vitro data suggest that the intracellular environment of cancer cells is capable of compromising the integrity of self-assembled nanoparticles and thus causes disruption of the tight dye packing inside the hydrophobic cores and activation of the NIR fluorescence. Animal studies demonstrated accumulation of activatable nanoparticles at the tumor site following systemic administration, as well as release and fluorescence recovery of SiNc from the polymeric carrier. It was also validated that the developed nanoparticles are compatible with the intraoperative imaging system Fluobeam® 800, and nanoparticle-mediated image-guided surgery provides successful resection of cancer tumors. Finally, in vivo studies revealed that combinatorial phototherapy mediated by the nanoparticles could efficiently eradicate chemoresistant ovarian cancer tumors. Conclusion: The revealed properties of the activatable nanoplatform make it highly promising for further application in clinical image-guided surgery and combined phototherapy, facilitating a potential translation to clinical studies.

LHRH-Targeted Drug Delivery Systems for Cancer Therapy.

Targeted delivery of therapeutic and diagnostic agents to cancer sites has significant potential to improve the therapeutic outcome of treatment while minimizing severe side effects. It is widely accepted that decoration of the drug delivery systems with targeting ligands that bind specifically to the receptors on the cancer cells is a promising strategy that may substantially enhance accumulation of anticancer agents in the tumors. Due to the transformed cellular nature, cancer cells exhibit a variety of overexpressed cell surface receptors for peptides, hormones, and essential nutrients, providing a significant number of target candidates for selective drug delivery. Among others, luteinizing hormonereleasing hormone (LHRH) receptors are overexpressed in the majority of cancers, while their expression in healthy tissues, apart from pituitary cells, is limited. The recent studies indicate that LHRH peptides can be employed to efficiently guide anticancer and imaging agents directly to cancerous cells, thereby increasing the amount of these substances in tumor tissue and preventing normal cells from unnecessary exposure. This manuscript provides an overview of the targeted drug delivery platforms that take advantage of the LHRH receptors overexpression by cancer cells.

Phototheranostic nanoplatform based on a single cyanine dye for image-guided combinatorial phototherapy.

This study represents a novel phototheranostic nanoplatform based on the near-infrared (NIR) heptamethine cyanine dye, IR775, which is capable of concurrent real-time fluorescence imaging and cancer eradication with combinatorial phototherapy. To achieve water solubility and enhance tumor delivery, the hydrophobic IR775 dye was loaded into a biocompatible polymeric nanoparticle with a diameter of ~40nm and slightly negative surface charge (-2.34mV). The nanoparticle-encapsulated hydrophobic IR775 dye (IR775-NP) is characterized by an enhanced fluorescence quantum yield (16%) when compared to the water soluble analogs such as ICG (2.7%) and IR783 (8%). Furthermore, the developed IR-775-NP efficiently generates both heat and reactive oxygen species under NIR light irradiation, eradicating cancer cells in vitro. Finally, animal studies revealed that the IR775-NP accumulates in cancer tumors after systemic administration, efficiently delineates them with NIR fluorescence signal and completely eradicates chemo resistant cancer tissue after a single dose of combinatorial phototherapy.

Cancer nanotheranostics: Strategies, promises and impediments.

Cancer has remained one of the most indomitable conundrums for scientists over centuries due to its multifarious etiology. While improved therapeutic and diagnostic approaches have commendably augmented the rate of survival of cancer patients, a holistic riddance from the ailment is still implausible. Hence, further explorations to scout for novel strategies of cancer therapy and diagnosis are necessary. Theranostics (amalgamation of therapy and diagnostics) has emerged as one of the avant-garde strategies, which provides a two-pronged advantage in cancer management. This integrative approach has found immense relevance in light of nanotechnology. Nanoparticles can be customized (loaded with a mélange of therapeutic drugs and diagnostic probes) to develop theranostic properties, thereby constructing nanotheranostic agents. These nano-composites are lucrative tools for cancer cell obliteration and simultaneous monitoring of the drug action, and can also be tailored for targeted drug delivery. Nanotheranostic agents have emerged as a prudent ploy for synchronized cancer intervention and detection of the 'route and reach' of the drugs. In this review, we discuss the diversified state-of-the-art facets of theranostic nanoparticles, including various nanoparticle-based platforms as well as the plethora of reported therapeutic drugs, aptamers, markers and diagnostic molecules that have found use in the precincts of nanotheranostics.

Mechanistic Nanotherapeutic Approach Based on siRNA-Mediated DJ-1 Protein Suppression for Platinum-Resistant Ovarian Cancer.

We report an efficient therapeutic modality for platinum resistant ovarian cancer based on siRNA-mediated suppression of a multifunctional DJ-1 protein that is responsible for the proliferation, growth, invasion, oxidative stress, and overall survival of various cancers. The developed therapeutic strategy can work alone or in concert with a low dose of the first line chemotherapeutic agent cisplatin, to elicit a maximal therapeutic response. To achieve an efficient DJ-1 knockdown, we constructed the polypropylenimine dendrimer-based nanoplatform targeted to LHRH receptors overexpressed on ovarian cancer cells. The quantitative PCR and Western immunoblotting analysis revealed that the delivered DJ-1 siRNA downregulated the expression of targeted mRNA and corresponding protein by more than 80% in various ovarian cancer cells. It was further demonstrated that siRNA-mediated DJ-1 suppression dramatically impaired proliferation, viability, and migration of the employed ovarian cancer cells. Finally, the combinatorial approach led to the most pronounced therapeutic response in all the studied cell lines, outperforming both siRNA-mediated DJ-1 knockdown and cisplatin treatment alone. It is noteworthy that the platinum-resistant cancer cells (A2780/CDDP) with the highest basal level of DJ-1 protein are most susceptible to the developed therapy and this susceptibility declines with decreasing basal levels of DJ-1. Finally, we interrogate the molecular underpinnings of the DJ-1 knockdown effects in the treatment of the ovarian cancer cells. By using various experimental techniques, it was revealed that DJ-1 depletion (1) decreases the activity of the Akt pathway, thereby reducing cellular proliferation and migration and increasing the antiproliferative effect of cisplatin on ovarian cancer cells; (2) enhances the activity of p53 tumor suppressor protein therefore restoring cell cycle arrest functionality and upregulating the Bax-caspase pathway, triggering cell death; and (3) weakens the cellular defense mechanisms against inherited oxidative stress thereby increasing toxic intracellular radicals and amplifying the reactive oxygen species created by the administration of cisplatin.

ROS-induced nanotherapeutic approach for ovarian cancer treatment based on the combinatorial effect of photodynamic therapy and DJ-1 gene suppression.

This study represents a novel approach for intraoperative ovarian cancer treatment based on the combinatorial effect of a targeted photodynamic therapy (PDT) associated with suppression of the DJ-1 protein, one of the key players in the ROS defense of cancer cells. To assess the potential of the developed therapy, dendrimer-based nanoplatforms for cancer-targeted delivery of near-infrared photosensitizer, phthalocyanine, and DJ-1 siRNA have been constructed. In vitro studies revealed that therapeutic efficacy of the combinatorial approach was enhanced when compared to PDT alone and this enhancement was more pronounced in ovarian carcinoma cells, which are characterized by higher basal levels of DJ-1 protein. Moreover, the ovarian cancer tumors exposed to a single dose of combinatorial therapy were completely eradicated from the mice and the treated animals showed no evidence of cancer recurrence. Thus, the developed therapeutic approach can be potentially employed intraoperatively to eradicate unresactable cancer cells. FROM THE CLINICAL EDITOR: The complete clearance of microscopic residual tumor cells during excision surgery is important to improve survival of the patient. In this interesting paper, the authors developed a novel approach using targeted photodynamic therapy (PDT), combining a photosensitizer, phthalocyanine, and DJ-1 siRNA for the treatment of ovarian cancer. The data showed that this approach increased cancer cell killing and may pave way for future clinical studies.

Phthalocyanine-loaded graphene nanoplatform for imaging-guided combinatorial phototherapy.

We report a novel cancer-targeted nanomedicine platform for imaging and prospect for future treatment of unresected ovarian cancer tumors by intraoperative multimodal phototherapy. To develop the required theranostic system, novel low-oxygen graphene nanosheets were chemically modified with polypropylenimine dendrimers loaded with phthalocyanine (Pc) as a photosensitizer. Such a molecular design prevents fluorescence quenching of the Pc by graphene nanosheets, providing the possibility of fluorescence imaging. Furthermore, the developed nanoplatform was conjugated with poly(ethylene glycol), to improve biocompatibility, and with luteinizing hormone-releasing hormone (LHRH) peptide, for tumor-targeted delivery. Notably, a low-power near-infrared (NIR) irradiation of single wavelength was used for both heat generation by the graphene nanosheets (photothermal therapy [PTT]) and for reactive oxygen species (ROS)-production by Pc (photodynamic therapy [PDT]). The combinatorial phototherapy resulted in an enhanced destruction of ovarian cancer cells, with a killing efficacy of 90%-95% at low Pc and low-oxygen graphene dosages, presumably conferring cytotoxicity to the synergistic effects of generated ROS and mild hyperthermia. An animal study confirmed that Pc loaded into the nanoplatform can be employed as a NIR fluorescence agent for imaging-guided drug delivery. Hence, the newly developed Pc-graphene nanoplatform has the significant potential as an effective NIR theranostic probe for imaging and combinatorial phototherapy.

Dendrimer-encapsulated naphthalocyanine as a single agent-based theranostic nanoplatform for near-infrared fluorescence imaging and combinatorial anticancer phototherapy.

Multifunctional theranostic platforms capable of concurrent near-infrared (NIR) fluorescence imaging and phototherapies are strongly desired for cancer diagnosis and treatment. However, the integration of separate imaging and therapeutic components into nanocarriers results in complex theranostic systems with limited translational potential. A single agent-based theranostic nanoplatform, therefore, was developed for concurrent NIR fluorescence imaging and combinatorial phototherapy with dual photodynamic (PDT) and photothermal (PTT) therapeutic mechanisms. The transformation of a substituted silicon naphthalocyanine (SiNc) into a biocompatible nanoplatform (SiNc-NP) was achieved by SiNc encapsulation into the hydrophobic interior of a generation 5 polypropylenimine dendrimer following surface modification with polyethylene glycol. Encapsulation provides aqueous solubility to SiNc and preserves its NIR fluorescence, PDT and PTT properties. Moreover, an impressive photostability in the dendrimer-encapsulated SiNc has been detected. Under NIR irradiation (785 nm, 1.3 W cm(-2)), SiNc-NP manifested robust heat generation capability (ΔT = 40 °C) and efficiently produced reactive oxygen species essential for PTT and PDT, respectively, without releasing SiNc from the nanopaltform. By varying the laser power density from 0.3 W cm(-2) to 1.3 W cm(-2) the therapeutic mechanism of SiNc-NP could be switched from PDT to combinatorial PDT-PTT treatment. In vitro and in vivo studies confirmed that phototherapy mediated by SiNc can efficiently destroy chemotherapy resistant ovarian cancer cells. Remarkably, solid tumors treated with a single dose of SiNc-NP combined with NIR irradiation were completely eradicated without cancer recurrence. Finally, the efficiency of SiNc-NP as an NIR imaging agent was confirmed by recording the strong fluorescence signal in the tumor, which was not photobleached during the phototherapeutic procedure.

Temperature-tunable iron oxide nanoparticles for remote-controlled drug release.

Herein, we report the successful development of a novel nanosystem capable of an efficient delivery and temperature-triggered drug release specifically aimed at cancer. The water-soluble 130.1 ± 0.2 nm iron oxide nanoparticles (IONPs) were obtained via synthesis of a monodispersed iron oxide core stabilized with tetramethylammonium hydroxide pentahydrate (TMAOH), followed by coating with the thermoresponsive copolymer poly-(NIPAM-stat-AAm)-block-PEI (PNAP). The PNAP layer on the surface of the IONP undergoes reversible temperature-dependent structural changes from a swollen to a collapsed state resulting in the controlled release of anticancer drugs loaded in the delivery vehicle. We demonstrated that the phase transition temperature of the prepared copolymer can be precisely tuned to the desired value in the range of 36°C-44°C by changing the monomers ratio during the preparation of the nanoparticles. Evidence of modification of the IONPs with the thermoresponsive copolymer is proven by ATR-FTIR and a quantitative analysis of the polymeric and iron oxide content obtained by thermogravimetric analysis. When loaded with doxorubicin (DOX), the IONPs-PNAP revealed a triggered drug release at a temperature that is a few degrees higher than the phase transition temperature of a copolymer. Furthermore, an in vitro study demonstrated an efficient internalization of the nanoparticles into the cancer cells and showed that the drug-free IONPs-PNAP were nontoxic toward the cells. In contrast, sufficient therapeutic effect was observed for the DOX-loaded nanosystem as a function of temperature. Thus, the developed temperature-tunable IONPs-based delivery system showed high potential for remotely triggered drug delivery and the eradication of cancer cells.

Multifunctional nanomedicine platform for concurrent delivery of chemotherapeutic drugs and mild hyperthermia to ovarian cancer cells.

A multifunctional tumor-targeting delivery system was developed and evaluated for an efficient treatment of drug-resistant ovarian cancer by combinatorial therapeutic modality based on chemotherapy and mild hyperthermia. The engineered iron oxide nanoparticle (IONPs)-based nanocarrier served as an efficient delivery vehicle for doxorubicin and provided the ability to heat cancer cells remotely upon exposure to an alternating magnetic field (AMF). The nanocarrier was additionally modified with polyethylene glycol and LHRH peptide to improve its biocompatibility and ability to target tumor cells. The synthesized delivery system has an average size of 97.1 nm and a zeta potential close to zero, both parameters favorable for increased stability in biological media and decreased elimination by the immune system. The nanocarrier demonstrated faster drug release in acidic conditions that mimic the tumor environment. It was also observed that the LHRH targeted delivery system could effectively enter drug resistant ovarian cancer cells, and the fate of doxorubicin was tracked with fluorescence microscope. Mild hyperthermia (40°C) generated by IONPs under exposure to AMF synergistically increased the cytotoxicity of doxorubicin delivered by the developed nanocarrier to cancer cells. Thus, the developed IONPs-based delivery system has high potential in the effective treatment of ovarian cancer by combinatorial approach.

A multifunctional theranostic platform based on phthalocyanine-loaded dendrimer for image-guided drug delivery and photodynamic therapy.

Owing to the outstanding near-infrared (NIR) optical properties, phthalocyanines (Pc) have promising potential as theranostic agents for fluorescence image-guided drug delivery and noninvasive treatment of deep tumors by photodynamic therapy (PDT). Nevertheless, clinical application of phthalocyanines is substantially limited by poor water solubility, aggregation and insufficient selectivity for cancer cells. To address these issues, we have developed a novel dendrimer-based theranostic platform for tumor-targeted delivery of phthalocyanines. The preparation procedure involved the modification of the Pc molecule with a hydrophobic linker, which significantly enhances physical encapsulation of the hydrophobic drug into a generation 4 polypropylenimine (PPI G4) dendrimer. In order to improve biocompatibility and tumor-targeted delivery, the surface of the resulting Pc-PPIG4 complexes was additionally modified with poly(ethylene glycol) (PEG) and luteinizing hormone-releasing hormone (LHRH) peptide, respectively. The developed nanocarriers have an average diameter of 62.3 nm and narrow size distribution with a polydispersity index of 0.100. The drug encapsulation efficiency was 20% w/w, and the synthesized phthalocyanine derivative entrapped in the dendrimer-based nanocarrier exhibits a distinct NIR absorption (700 nm) and fluorescence emission (710 and 815 nm), required for an efficient PDT and fluorescence imaging. It was demonstrated that subcellular localization in vitro and organ distribution in vivo of the developed nanocarrier can be determined based on the intrinsic fluorescence properties of encapsulated phthalocyanine, validating its role as an imaging agent. The imaging experiments revealed that the LHRH targeted nanocarrier is capable of an efficient internalization into cancer cells as well as tumor accumulation when intravenously administered into mice. Finally, the prepared formulation exhibited low dark cytotoxicity (IC50=28 µg/mL) while light irradiation of the cancer cells transfected with the developed theranostic agents resulted in significant PDT effects (IC50=0.9 µg/mL) through excessive generation of toxic reactive oxygen species. Thus, the obtained results demonstrated significant potential of the designed dendrimer-based nanocarrier as an efficient NIR theranostic agent.

Aphid fecundity and grassland invasion: invader life history is the key.

Loss or gain of pathogens can determine the trajectory of biological invasions, and invasion by novel hosts also can alter pathogen dynamics to facilitate invasion. Recent empirical and theoretical work has implicated infection by barley and cereal yellow dwarf viruses (B/CYDV), a group of generalist pathogens of the Poaceae family (grasses), as a necessary precursor to the invasion of over 9 million hectares of California's perennial grasslands by exotic annual grasses. The mechanism underlying this pathogen-mediated invasion hypothesis is elevated vector fecundity on exotic annual grasses. While empirical evidence supports this hypothesis, the links between aphid fecundity, host identity, and host resource supply have not been thoroughly assessed. We performed field and laboratory experiments to examine the fecundity and preference responses of three of the most common aphid vectors of B/CYDV, Rhopalosiphum padi (L.), R. maidis (Fitch), and Sitobion avenae (Fab.), to a combination of host life history (annual and perennial), host provenance (native and exotic), and nutrient supply (mineral N and P fertilization), controlling for host phylogenetic lineage. Aphids consistently had higher fecundity on annual grasses than perennials, regardless of host provenance, age, or nutrient fertilization. In addition, aphids preferentially colonized annual hosts when offered a choice among host species. Multi-generation studies have found that nutrient addition affects both host quality and composition in natural communities; our experimental results indicate that the indirect effects of nutrient fertilization in determining host community composition are of more importance than are the direct effects on host quality to aphid population dynamics. To summarize the applications of our results, we demonstrate that, in contrast to the current focus on the qualitative differences between invaders and natives, the impact of invasive exotic grasses is not due to host provenance, per se, but arises because the annual invaders differ qualitatively from the native species in interactions with shared pathogen vectors. More generally, our work demonstrates the importance of isolating whether the fate and impacts of an invader are, at their root, due to the provenance of the invader, or due to other characteristics that determine its functional uniqueness in the context of the native community.