Potential Natural Products Regulation of Molecular Signaling Pathway in Dermal Papilla Stem Cells.

Stem cells have demonstrated significant potential for tissue engineering and repair, anti-aging, and rejuvenation. Hair follicle stem cells can be found in the dermal papilla at the base of the follicle and the bulge region, and they have garnered increased attention because of their potential to regenerate hair as well as their application for tissue repair. In recent years, these cells have been shown to affect hair restoration and prevent hair loss. These stem cells are endowed with mesenchymal characteristics and exhibit self-renewal and can differentiate into diverse cell types. As research in this field continues, it is probable that insights regarding stem cell maintenance, as well as their self-renewal and differentiation abilities, will benefit the application of these cells. In addition, an in-depth discussion is required regarding the molecular basis of cellular signaling and the influence of nature-derived compounds in stimulating the stemness properties of dermal papilla stem cells. This review summarizes (i) the potential of the mesenchymal cells component of the hair follicle as a target for drug action; (ii) the molecular mechanism of dermal papilla stem cells for maintenance of their stem cell function; and (iii) the positive effects of the natural product compounds in stimulating stemness in dermal papilla stem cells. Together, these insights may help facilitate the development of novel effective hair loss prevention and treatment.

Redox/photo dual-responsive, self-targeted, and photosensitizer-laden bismuth sulfide nanourchins for combination therapy in cancer.

Targeted and stimuli-sensitive nanobombs for the release of therapeutic agents after laser irradiation of the tumor site are gaining widespread attention as personalized anticancer regimens. In this study, redox and photo dual-responsive, folate receptor-targeted nanourchin carriers for chemo-, photodynamic, and photothermal therapy were constructed by the amalgamation of an outer layer of polyethylene glycol (PEG)-S-S-methotrexate (MTX) and an inner core of indocyanine green (ICG)-loaded bismuth sulfide (Bi2S3) nanoparticles for cancer treatment. MTX introduces the carrier to folate receptors resulting in the internalization of nanoparticles into cancer cells, specifically and increasingly. In the reducing environment inside cancer cells, MTX was cleaved, resulting in a burst release that effectively inhibited tumor growth. Simultaneously, the fusion of Bi2S3 and ICG in the inner core absorbed energy from a near-infrared radiation (NIR) laser to generate heat and reactive oxygen species, which further ablated the tumors and synergistically enhanced the anticancer activity of MTX. These results indicate the successful preparation of combined nanourchins (NUs) showing GSH-induced and laser-responsive release of MTX and ICG, accompanied by hyperthermia via Bi2S3 and ICG. Effective in vitro cellular internalization, cellular cytotoxicity, and pro-apoptotic behavior of the nanosystem were achieved through a targeting, redox, and NIR-responsive combination strategy. In vivo biodistribution and photothermal imaging also revealed tumor-selective and -retentive, as well as thermally responsive attributes. Ultimately, this in vivo antitumor study shows an effective tumor ablation by these nanourchins without affecting the vital organs. Our findings indicate that using these targeted redox- and laser-responsive combination therapeutic carriers can be a promising strategy in folate receptor-expressing tumors.

Stealth Polymer-Coated Graphene Oxide Decorated Mesoporous Titania Nanoplatforms for In Vivo Chemo-Photodynamic Cancer Therapy.

PURPOSE: The goal of this study was to develop chemotherapeutic drug-loaded photoactivable stealth polymer-coated silica based- mesoporous titania nanoplatforms for enhanced antitumor activity. METHODS: Both in vitro and in vivo models of solvothermal treated photoactivable nanoplatforms were evaluated for efficient chemo-photothermal activity. A versatile nanocomposite that combined silica based- mesoporous titania nanocarriers (S-MTN) with the promising photoactivable agent, graphene oxide (G) modified with a stealth polymer (P) was fabricated to deliver chemotherapeutic agent, imatinib (I), (referred as S-MTN@IG-P) for near-infrared (NIR)-triggered drug delivery and enhanced chemo-photothermal therapy. RESULTS: The fabricated S-MTN@IG-P nanoplatform showed higher drug loading (~20%) and increased drug release (~60%) in response to light in acidic condition (pH 5.0). As prepared nanoplatform significantly converted NIR light into thermal energy (43.2°C) to produce reactive oxygen species (ROS). The pronounced cytotoxic effect was seen in both colon cancer cells (HCT-116 and HT-29) that was mediated through the chemotherapeutic effect of imatinib and the photothermal and ROS generation effects of graphene oxide. In vivo study also showed that S-MTN@IG-P could significantly accumulate into the tumor area and suppress the tumor growth under NIR irradiation without any biocompatibility issues. CONCLUSION: Cumulatively, the above results showed promising effects of S-MTN@IG-P for effective chemo-phototherapy of colon cancer.

Phytosterol-loaded CD44 receptor-targeted PEGylated nano-hybrid phyto-liposomes for synergistic chemotherapy.

Background: Phytosterols significantly reduce the risk of cancer by directly inhibiting tumor growth, inducing apoptosis, and inhibiting tumor metastasis. Stigmasterol (STS), a phytosterol, exhibits anticancer effects against various cancers, including breast cancer. Chemotherapeutics, including doxorubicin (DOX), might act synergistically with phytosterol against the proliferation and metastasis of breast cancer. Although such compounds can show potential anticancer activity, their combined effect with suitable formulation has not investigated yet.Methods: Hyaluronic acid (HA)-modified PEGylated DOX-STS loaded phyto-liposome was fabricated via a thin-film hydration method. The prepared phyto-liposome was optimized with regards to its physicochemical and other properties. Further, in vitro and in vivo study was carried out in breast cancer cells expressing a different level of CD44 receptors.Results: The particle size of prepared HA-DOX-STS-lipo was 173.9 ± 2.4 nm, and showed pH-depended DOX release, favoring the effective tumor targetability. The in vitro anticancer activity of HA-DOX-STS-lipo was significantly enhanced in MDA-MB-231, CD44-overexpressing cells relative to MCF-7 cells demonstrating HA-mediated targeting effect. HA-DOX-STS-lipo accumulated more and increased antitumor efficacy in the MDA-MB-231 xenograft tumor model expressing high levels of CD44, suggesting the potential of carrier system toward CD44-overexpressing tumors.

Development of Folate-Functionalized PEGylated Zein Nanoparticles for Ligand-Directed Delivery of Paclitaxel.

In this study, we investigated the active targeted delivery of a hydrophobic drug, paclitaxel (PTX), via receptor-mediated endocytosis by folate receptors expressed on cancer cells using a protein-based nanoparticle system. PTX was loaded on zein nanoparticles and conjugated with folate (PTX/Zein-FA) to estimate its chemotherapeutic efficacy in folate receptor-expressing KB cancer cells. PTX/Zein-FA nanoparticles were successfully developed, with a nanoparticle size of ~180 nm and narrow polydispersity index (~0.22). Accelerated release of PTX in an acidic environment was observed for PTX/Zein-FA. An in vitro cellular study of PTX/Zein-FAs in KB cells suggested that PTX/Zein-FA improved the cytotoxic activity of PTX on folate receptors overexpressed in cancer cells by inducing proapoptotic proteins and inhibiting anti-apoptotic proteins. In addition, PTX/Zein-FA exhibited anti-migratory properties and could alter the cell cycle profile of KB cells. A549 cells, which are folate receptor-negative cancer cells, showed no significant enhancement in the in vitro cellular activities of PTX/Zein-FA. We describe the antitumor efficacy of PTX/Zein-FA in KB tumor-bearing mice with minimum toxicity in healthy organs, and the results were confirmed in comparison with free drug and non-targeted nanoparticles.

Tailored Black Phosphorus for Erythrocyte Membrane Nanocloaking with Interleukin-1α siRNA and Paclitaxel for Targeted, Durable, and Mild Combination Cancer Therapy.

Several therapeutic nanosystems have been engineered to remedy the shortcomings of cancer monotherapies, including immunotherapy (stimulating the host immune system to eradicate cancer), to improve therapeutic efficacy with minimizing off-target effects and tumor-induced immunosuppression. Light-activated components in nanosystems confer additional phototherapeutic effects as combinatorial modalities; however, systemic and thermal toxicities with unfavorable accumulation and excretion of nanoystem components now hamper their practical applications. Thus, there remains a need for optimal multifunctional nanosystems to enhance targeted, durable, and mild combination therapies for efficient cancer treatment without notable side effects. Methods: A nanosystem constructed with a base core (poly-L-histidine [H]-grafted black phosphorus [BP]) and a shell (erythrocyte membrane [EM]) is developed to offer a mild photoresponsive (near-infrared) activity with erythrocyte mimicry. In-flight electrostatic tailoring to extract uniform BP nanoparticles maintains a hydrodynamic size of <200 nm (enabling enhanced permeability and retention) after EM cloaking and enhances their biocompatibility. Results: Ephrin-A2 receptor-specific peptide (YSA, targeting cancer cells), interleukin-1α silencing small interfering RNA (ILsi, restricting regulatory T cell trafficking), and paclitaxel (X, inducing durable chemotherapeutics) are incorporated within the base core@shell constructs to create BP-H-ILsi-X@EM-YSA architectures, which provide a more intelligent nanosystem for combination cancer therapies. Conclusion: The in-flight tailoring of BP particles provides a promising base core for fabricating <200 nm EM-mimicking multifunctional nanosystems, which could be beneficial for constructing smarter nanoarchitectures to use in combination cancer therapies.

Regulatory T Cells Tailored with pH-Responsive Liposomes Shape an Immuno-Antitumor Milieu against Tumors.

Cell-based delivery platforms have received great interest in recent years and have been indicated as a promising strategy for cancer immunotherapy. Despite their wide applications in the clinical and preclinical stages, their concomitant viability and efficacy remain major issues. Herein, a strategy for harnessing regulatory T (Treg) cells is developed as an actively targeting drug-delivery system to transport drug-loaded liposomes to the desired tumor sites via conjugating liposomes on the surface of Treg cells. Under the guidance of tumor-oriented chemokines, liposome-anchored Treg cells can be leveraged to migrate and infiltrate the acidic tumor microenvironment, where pH-sensitive liposomes release the loaded cargos [comprising interleukin-2, programmed cell death ligand 1 antibody (PD-L1), and imiquimod], provoke dramatic dendritic cell maturation, block the PD-1/PD-L1 immune-checkpoint, elevate the frequency of infiltrating CD8+ effector T cells, and collectively contribute to potent inhibition of in situ and metastatic tumors. Here, the findings suggest a potential approach that offers a simple, robust, and safe insight into the tuning of Treg cells as an encouraging vector for augmenting cancer immunotherapy.

Multifaceted NIR-responsive polymer-peptide-enveloped drug-loaded copper sulfide nanoplatform for chemo-phototherapy against highly tumorigenic prostate cancer.

Targeted, biocompatible, and synergistic "all in one" systems should be designed to combat the heterogeneity of cancer. In this study, we constructed a dual function nanosystem, copper sulfide nanoplatform loaded with the chemotherapeutic drug docetaxel wrapped by a conjugated polymer-peptide for targeted chemo-phototherapy. The nanoconstruct has been successfully designed with a size of 186.1 ±â€¯5.2 nm, a polydispersity index of 0.18 ±â€¯0.01, and zeta potential of -16.4 ±â€¯0.1 mV. The enhanced uptake and near-infrared-responsive behavior of the nanosystem resulted in efficient drug release, photothermal ablation, effective cytotoxic activity, and potentiated reactive oxygen species generation. The induction of apoptotic markers, enhanced accumulation in the tumor site, and maximum tumor growth inhibition were seen during in vivo studies compared to non-targeted nanoformulations and free drug. Cumulatively, our results indicate that, with low systemic toxicity and better biocompatibility, this nanoconstruct could provide a promising strategy for treating prostate cancer.

Aerosol technique-based carbon-encapsulated hollow mesoporous silica nanoparticles for synergistic chemo-photothermal therapy.

Near-infrared (NIR)-responsive drug delivery systems have enhanced tumor ablative efficiency through permeation and retention effects. Graphene oxide (GO) has shown great potential both in photothermal therapy and in drug delivery. Thus, in this study, we designed an ambient spark-generated GO, wrapped on topotecan (TPT)-loaded hollow mesoporous silica nanoparticles (HMSN-NH2-TPT-CGO), to function as an efficient platform for pH-dependent sustained release of TPT. HMSN-NH2-TPT-CGO also exhibited a combined chemo-photothermal effect within a single carrier system. This developed system was stable with a uniform particle size (∼190 nm) and was demonstrated to possess a sufficient heat-absorbing capacity to induce tumor cell ablation. We performed the ablation of tumor cells both in vitro and in vivo in combination with photothermal therapy and chemotherapy using the spark-generated functional GO and HMSN. The prepared nanocarriers demonstrated high cellular uptake, apoptosis, and G0/G1 cell cycle arrest. In vivo study using the MDA-MB-231 xenograft model revealed the ultraefficient tumor ablative performance of HMSN-NH2-TPT-CGO compared with that of free TPT, with no toxic effect on vital organs. Altogether, the optimized nanocarriers presented a significant potential to act as a vehicle for cancer treatment. STATEMENT OF SIGNIFICANCE: This is the first study that uses spark-generated graphene oxide nanoflakes to cover the topotecan (TPT)-loaded hollow mesoporous silica nanoparticles (HMSNs) to treat breast cancer. Dense silica was used as a hard template to prepare the HMSNs attributing to a high drug payload. The concentration of Na2CO3 was precisely controlled to minimize the silica etching time within 70 min. The use of the nanographene flakes served a dual purpose, first, by acting as a capping agent to prevent the premature release of drug and, second, by serving as a nano heater that significantly ablates the tumor cells. The prepared nanocarriers (NCs) exhibited effective and enhanced in vitro and in vivo apoptosis, as well as significant tumor growth inhibition even after 15 days of treatment time, with no toxic effect to the vital organs. The NCs enhanced in vitro tumor cell killing effects and served as an effective carrier for in vivo tumor regression, thereby highlighting the enormous potential of this system for breast cancer therapy.

Transferrin-Conjugated Polymeric Nanoparticle for Receptor-Mediated Delivery of Doxorubicin in Doxorubicin-Resistant Breast Cancer Cells.

In this study, a transferrin (Tf)-conjugated polymeric nanoparticle was developed for the targeted delivery of the chemotherapeutic agent doxorubicin (Dox) in order to overcome multi-drug resistance in cancer treatment. Our objective was to improve Dox delivery for producing significant antitumor efficacy in Dox-resistant (R) breast cancer cell lines with minimum toxicity to healthy cells. The results of our experiments revealed that Dox was successfully loaded inside a transferrin (Tf)-conjugated polymeric nanoparticle composed of poloxamer 407 (F127) and 123 (P123) (Dox/F127&P123-Tf), which produced nanosized particles (~90 nm) with a low polydispersity index (~0.23). The accelerated and controlled release profiles of Dox from the nanoparticles were characterized in acidic and physiological pH and Dox/F127&P123-Tf enhanced Dox cytotoxicity in OVCAR-3, MDA-MB-231, and MDA-MB-231(R) cell lines through induction of cellular apoptosis. Moreover, Dox/F127&P123-Tf inhibited cell migration and altered the cell cycle patterns of different cancer cells. In vivo study in MDA-MB-231(R) tumor-bearing mice demonstrated enhanced delivery of nanoparticles to the tumor site when coated in a targeting moiety. Therefore, Dox/F127&P123-Tf has been tailored, using the principles of nanotherapeutics, to overcome drug-resistant chemotherapy.

Transferrin-conjugated pH-sensitive platform for effective delivery of porous palladium nanoparticles and paclitaxel in cancer treatment.

Porous palladium (Pd) nanoparticles have garnered great research attention due to their potential anticancer activity and photothermal effect. In this study, a transferrin-conjugated pH-sensitive platform (Tf-PPP), comprising porous Pd nanoparticles (PdNPs) and paclitaxel (PTX), was successfully developed for combined chemo-phototherapy. Tf-PPPs have a small size of 164.6 ± 8.7 nm, PDI of 0.278 ± 0.029, and negative charge (-13.2 ± 1.8 mV). Poly(acrylic acid)-poly(ethylene oxide) (PAA-PEO), a pH sensitive polymer, was used to achieve pH-dependent drug release from nanoparticles. Transferrin (Tf) conjugated on the surface of nanoplatforms could enhance the cellular uptake and prolong nanoparticle accumulation in the tumor site. The combination of phototherapy induced by PdNPs and chemotherapeutic agent (PTX) could exhibit synergistic anticancer activities. Consistent findings were observed in both in vitro experiments including cytotoxicity, live/dead assay, and assessment of apoptotic protein levels, and in vivo antitumor study in MCF-7 tumor-bearing mice, with results decreasing in the following order: Tf-PPPs + NIR > Tf-PPPs > PPPs + NIR > PPPs > PTX > PdNPs. These findings suggest that the administration of Tf-PPPs, followed by NIR irradiation could be a promising strategy in the treatment of cancer.

Folate-targeted nanostructured chitosan/chondroitin sulfate complex carriers for enhanced delivery of bortezomib to colorectal cancer cells.

Folate-targeting self-assembled nanoparticles (NPs) using biocompatible and biodegradable natural polymers chitosan (Cs) and chondroitin sulfate (Chs) were developed to address the major challenge in cancer treatment, the selective delivery of nanoparticles to the target site. In this study, we successfully incorporated a hydrophobic drug, bortezomib (Bor), into folic acid (FA)-conjugated Cs/Chs self-assembled NPs (Bor/Cs/Chs-FA) for colorectal cancer therapy. The particle size and polydispersity index of Bor/Cs/Chs-FA were ∼196.5 ±â€¯1.2 nm and ∼0.21 ±â€¯0.5, respectively. A pH-dependent release profile was observed, facilitating cancer cell-targeted drug release under an acidic tumor microenvironment. Moreover, in vitro data revealed enhanced cellular uptake and apoptosis in folate receptor-expressing colorectal cancer cells (HCT-116 and HT-29) as compared to that in lung cancer cells (A549), which do not express folate receptors. Furthermore, intravenous administration of Bor/Cs/Chs-FA in a HCT-116 bearing xenograft mouse model showed that the NPs were a safe and effective drug delivery system. The results suggest that folate-targeted nanoparticle can be effectively applied for efficient chemotherapy of colorectal cancer.

Combination of NIR therapy and regulatory T cell modulation using layer-by-layer hybrid nanoparticles for effective cancer photoimmunotherapy.

The efficacy of combined near-infrared (NIR) and immune therapies for inhibiting tumor growth and recurrence has gained increasing research attention. Regulatory T cells in the tumor microenvironment constitute a major obstacle in achieving robust CD8+ T cell antitumor immunotherapy. In the present study, we designed a photoimmunotherapy-based strategy involving a combination of photothermal and photodynamic therapies, followed by Treg cell suppression, for eliciting an immune response with IR-780- and imatinib-loaded layer-by-layer hybrid nanoparticles. Methods: The layer-by-layer hybrid nanoparticles were prepared through electrostatic interactions. Their photothermal effect, photodynamic effect as well as their effect on inhibiting Treg cells' suppressive function were investigated in vitro and in vivo. Their antitumor effect was evaluated using B16/BL6 and MC-38 tumor-bearing mice. Results: The layer-by-layer hybrid nanoparticles, which were pH-sensitive, enabled the release of IR-780 dye for NIR-induced photothermal and photodynamic effects, and the release of imatinib-loaded glucocorticoid-induced TNF receptor family-related protein/poly(lactic-co-glycolic acid) (GITR-PLGA) nanoparticles to initiate antitumor immunotherapy. The photothermal and photodynamic effects caused by IR-780 under NIR exposure resulted in direct tumor apoptosis/necrosis and the production of tumor-associated antigen, promoted dendritic cell maturation, and enhanced the presentation of tumor-associated antigen to T cells, while the imatinib-loaded GITR-PLGA cores reduced the suppressive function of Treg cells, and consequently activated effective CD8+ T cells towards tumors. Conclusion: With the significant photothermal, photodynamic and immunotherapies, the system successfully eradicated tumor growth, diminished tumor recurrence, and improved survival in vivo. The proposed nanoparticles provide a novel and versatile approach to boost antitumor photoimmunotherapy.

Folate receptor-mediated celastrol and irinotecan combination delivery using liposomes for effective chemotherapy.

Drug targeting using functionalized nanoparticles provides a new standard in anticancer therapy. Liposomes, safe and effective drug delivery carriers, can incorporate both hydrophilic and hydrophobic drugs for combination chemotherapy treatment of cancers. The objectives of the current study were to synthesize and test the effectiveness of a nanotechnology-based strategy utilizing folic acid (FA)-conjugated liposomes that incorporate both celastrol (Cs) and irinotecan (Ir) for targeted breast cancer therapy. Our results revealed the successful preparation of Cs and Ir-loaded folate-targeted liposomes (Lipo/Cs/Ir-FA) with a small particle size (∼190 nm) and polydispersity index (∼0.10). The formulation exhibited higher drug release profiles for both Ir and Cs at pH 5.0 compared to those at physiological pH, favoring cancer cell-targeted release. Furthermore, in vitro cell studies showed high uptake and enhanced apoptosis in folate receptor-positive breast cancer cells (MCF-7 and MDA-MB-231), but not in folate receptor-negative lung cancer cells (A549). Moreover, an in vivo study in a mouse tumor model using MDA-MB-231 xenografts supported effective drug delivery behavior of the folate-conjugated liposomes by selective targeting of tumor tissue and minimizing systemic adverse effects. Therefore, our formulation could provide an effective therapy for targeted cancer treatment.

In situ fabrication of mesoporous silica-coated silver-gold hollow nanoshell for remotely controllable chemo-photothermal therapy via phase-change molecule as gatekeepers.

This study reports a new strategy for in situ fabrication of plasmonic hollow silver-gold nanoshell (with resonance tuned to NIR region) encased in the hollow mesoporous silica as an efficient platform to efficiently and precisely regulate the release of 5-fluorouracil (anticancer drug) for prostate cancer therapy and photothermal therapy. The mesopores were capped with thermosensitive phase-change material lauric acid, which allowed for remote, precise, and spatiotemporal control of drug release via external heating or photothermal heating of plasmonic silver-gold nanoshell via NIR laser irradiation. The system was nanometric, monodispersed, and showed negative surface charge. The nanocarrier showed better pH stability and thermodynamic stability compared to dense silica-coated gold nanoshells. The drug release could be triggered remotely by applying low powered continuous wave NIR laser (λ = 808 nm). The nanocarrier showed improved internalization by cancer cells, which was further enhanced by laser irradiation. High powered laser directly killed the cancer cells via photothermal effect in the region irradiated. Thus, this system fabricated by novel synthetic strategy provided efficient chemo- and phototherapy.

Palladium nanoparticle-decorated 2-D graphene oxide for effective photodynamic and photothermal therapy of prostate solid tumors.

Intratumoral injection of nanoparticles is a viable alternative for treating solid tumors. In this study, we used intratumorally-injected palladium nanoparticle (Pd NP)-decorated graphene oxide (GO) (GO-Pd NPs) for the treatment of solid prostate tumors. GO was synthesized using the modified Hummer's method and GO-Pd NPs were prepared using the one pot synthesis method. Studies on physicochemical characterization and in vitro/in vivo anticancer properties were performed using GO-Pd NPs. Successful preparation of GO-Pd NPs was confirmed by transmission electron microscopy, Fourier transform infrared spectroscopy, energy dispersive X-ray spectroscopy, and X-ray photoelectron spectroscopy. Compared to GO or Pd NPs alone, GO-Pd NPs showed higher cytotoxic effects in prostate cancer 3 (PC3) cells. Irradiation of treated cells with near infrared (NIR) laser considerably enhanced apoptosis induced by synergistic photothermal effect and reactive oxygen species (ROS) generation. Intratumorally-injected GO-Pd NPs showed promising in vivo localized distribution, photothermal ablation, and anti-tumor effects in the PC3 xenograft mouse model. Furthermore, the minimal organ toxicity of GO-Pd NPs was an added advantage. Hence, GO-Pd NPs could be a potential formulation for localized treatment of prostate solid tumors.

Regulatory T cell-targeted hybrid nanoparticles combined with immuno-checkpoint blockage for cancer immunotherapy.

Immunosuppression in tumor microenvironments induced by regulatory T (Treg) cells is regarded a critical mechanism of tumor immune escape and poses a major impediment to cancer immunotherapy. In this study, we developed tLyp1 peptide-conjugated hybrid nanoparticles for targeting Treg cells in the tumor microenvironment. The tLyp1 peptide-modified hybrid nanoparticles presented good stability and effective targeting to Treg cells, and they enhanced the effect of imatinib in downregulating Treg cell suppression through inhibition of STAT3 and STAT5 phosphorylation. In addition, an in vivo study revealed high tumor accumulation of the hybrid nanoparticle. Specifically, prolonged survival rate, enhanced tumor inhibition, reduced intratumoral Treg cells, and elevated intratumoral CD8+ T cells against tumor were observed when combined with checkpoint-blockade by using anti-cytotoxic T-lymphocyte antigen-4 antibody. This study provided groundwork for a repertoire of nanoparticle-based drugs for targeting and modulating Treg cell function in the tumor microenvironment and for improving antitumor immunotherapy.