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Qian Xie,1,* Shi Gao,1,* Rui Tian,2 Guohao Wang,3,4 Zainen Qin,5 Minglong Chen,1 Wenhui Zhang,1 Qiang Wen,1 Qingjie Ma,1 Lei Zhu1 1Department of Nuclear Medicine, China-Japan Union Hospital of Jilin University, NHC Key Laboratory of Radiobiology, School of Public Health of Jilin University, Changchun, 130033, People’s Republic of China; 2Department of Ophthalmology Second Hospital, Jilin University, Changchun, 130033, People’s Republic of China; 3Cancer Centre, Faculty of Health Sciences, University of Macau, Macau, SAR, 999078, People’s Republic of China; 4Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Macau, SAR, 999078, People’s Republic of China; 5Department of Oral Radiology, Guangxi Medical University College of Stomatology, Nanning, 530021, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qingjie Ma; Lei Zhu, Email maqj@jlu.edu.cn; zeh.ray8@gmail.comIntroduction: Combination therapy is a promising approach to promote the efficacy and reduce the systemic toxicity of cancer therapy. Herein, we examined the potency of a combined chemo-phototherapy approach by constructing a hyaluronidase- and reactive oxygen species-responsive hyaluronic acid nanoparticle carrying a chemotherapy drug and a photosensitizer in a tumor-bearing mouse model. We hypothesized that following decomposition, the drugs inside the nanocomplex will be released in the tumors to provide effective tumor treatment. We aimed to design a smart drug delivery system that can improve traditional chemotherapy drug delivery and enhance the therapeutic efficacy in combination with photodynamic therapy.Methods: Hydrophilic hyaluronic acid (HA) was covalently modified with a hydrophobic 5β-cholanic acid (CA) via an ROS-cleavable thioketal (tk) linker for a targeted co-deliver of 10-Hydroxy camptothecin (HCPT) and Chlorin e6 (Ce6) into tumors to improve the efficiency of combined chemo-photodynamic therapy.Results: The obtained HA-tk-CA nanoparticle carrying HCPT and Ce6, named HTCC, accumulated in the tumor through the enhanced permeable response (EPR) effect and HA-mediated CD44 targeting after intravenous administration. Upon laser irradiation and hyaluronidase degradation, HTCC was disrupted to release HCPT and Ce6 into the tumors. Compared to the monotherapy approach, HTCC demonstrated enhanced tumor growth inhibition and minimized systemic toxicity in a tumor-bearing mouse model.Conclusion: Our results suggested that controlled dual-drug release not only improved tumor drug delivery efficacy, but also reduced systemic side effects. In addition to HCPT and Ce6 delivery, the HA-tk-CA nanocomplex can be used to deliver other drugs in synergistic cancer therapy. Since most current combined therapy uses free drugs with distinct spatiotemporal distributions, the simultaneous co-delivery of dual drugs with a remote on-demand drug delivery nanosystem provides an alternative strategy for drug delivery design.Keywords: chemotherapy, photodynamic therapy, hyaluronic acid, responsive nanoparticle, drug delivery

Three-dimensional (3D) bioink with favorable printability, strength, and biocompatibility challenged the 3D bioprinting technology in cartilage tissue engineering. Herein, we innovatively fabricated photo-crosslinkable methacrylated konjac glucomannan (KGMMA) as a novel biomaterial ink for 3D extrusion bioprinting in an attempt to construct precisely patterned tissues. Specifically, konjac glucomannan (KGM) was modified by methacrylic anhydride, which is a kind of photoreactive group, to form KGMMA. After UV crosslinking, the printed KGMMA hydrogel formed a covalent crosslinking network with high strength, desired shearing, and swelling and degradation characteristics. The properties of the KGMMA hydrogel could be modulated by changing the contents of MA. The shear-thinning property of the KGMMA biomaterial ink enables excellent printability, which can print different shapes including lattices, hexagons, and flowers. Furthermore, the bioinks support cell growth after being printed with chondrocytes for a culture. Therefore, the biodegradable, injectable, and photo-crosslinkable KGMMA biomaterial ink holds a great promise for cartilage tissue engineering.

Graphical Abstract Stimulus-responsive therapy that allows precise imaging-guided therapy is limited for osteoarthritis (OA) therapy due to the selection of proper physiological markers as stimulus. Based on that the over-production of Reactive Oxygen Species (ROS) is associated with the progression in OA, we selected ROS as markers and designed a cartilage targeting and ROS-responsive theranostic nanoprobe that can be used for effective bioimaging and therapy of OA. This nanoprobe was fabricated by using PEG micelles modified with ROS-sensitive thioketal linkers (TK) and cartilage-targeting peptide, termed TKCP, which was then encapsulated with Dexamethasone (DEX) to form TKCP@DEX nanoparticles. Results showed that the nanoprobe can smartly “turn on” in response to excessive ROS and “turn off” in the normal joint. By applying different doses of ROS inducer and ROS inhibitor, this nanoprobe can emit ROS-dependent fluorescence according to the degree of OA severity, helpful to precise disease classification in clinic. Specifically targeting cartilage, TKCP@DEX could effectively respond to ROS and sustained release DEX to remarkably reduce cartilage damage in the OA joints. This smart, sensitive and endogenously activated ROS-responsive nanoprobe is promising for OA theranostics. Supplementary Information The online version contains supplementary material available at 10.1186/s12951-021-01136-4.

Cannabidiol (CBD) is a non-intoxicating cannabinoid from cannabis sativa that has demonstrated efficacious against inflammation, which can be considered as a potential drug for arthritis treatment. However, the poor solubility and low bioavailability limit its clinical application. Here, we report an effective strategy to fabricate CBD-loaded poly lactic-co-glycolic acid nanoparticles (CBD-PLGA-NPs). The CBD-PLGA-NPs exhibited a spherical morphology and an average diameter of 238 nm. CBD was sustained release from CBD-PLGA-NPs, which improved the bioavailability of CBD. Primary chondrocytes from rat pups were isolated, and LPS was used to induce inflammation in vitro to simulate osteoarthritis (OA). The CBD-PLGA-NPs effectively protect the damage of LPS to cell viability. What’s more, according to the results of CCK-8 assay, hematoxylin-eosin staining, safranin O staining, immunofluorescence staining, and real-time polymerase chain reaction assay, we observed that CBD-PLGA-NPs significantly suppressed LPS-induced primary rat chondrocyte expression of inflammatory cytokines, including interleukin 1β (IL-1β), interleukin 6 (IL-6), tumor necrosis factor-α (TNF-α) and matrix metalloproteinase 13 (MMP-13). Remarkably, CBD-PLGA-NPs also showed better therapeutic effects of inhibiting the degradation of the extracellular matrix of chondrocytes than equivalent CBD solution. In general, the fabrication CBD-PLGA-NPs showed good protection of primary chondrocytes in vitro and is a promising system for osteoarthritis treatment. Significance of the study Cannabidiol (CBD) is a non-intoxicating cannabinoid from cannabis sativa that has demonstrated efficacious against inflammation, which can be considered as a potential drug for arthritis treatment. In order to improve the poor solubility and low bioavailability of CBD, we described the development of simple and efficient CBD-loaded nanoparticles (CBD-PLGA-NPs) for treating LPS-induced primary chondrocytes of rat pups damaged. The fabricated CBD-PLGA-NPs could effectively enhance the chondroprotective effects of CBD by inhibiting the expression of inflammatory factors, increasing cellularity, and improving structural changes, which can be regarded as a potential system to treat OA.

Intra-articular (IA) injection is an efficient treatment for osteoarthritis, which will minimize systemic side effects. However, the joint experiences rapid clearance of therapeutics after intra-articular injection. Delivering system modified through active targeting strategies to facilitate localization within specific joint tissues such as cartilage is hopeful to increase the therapeutic effects. In this study, we designed a nanoscaled amphiphilic and cartilage-targeting polymer-drug delivery system by using formononetin (FMN)-poly(ethylene glycol) (PEG) (denoted as PCFMN), which was prepared by PEGylation of FMN followed by coupling with cartilage-targeting peptide (CollBP). Our results showed that PCFMN was approximately regular spherical with an average diameter about 218 nm. The in vitro test using IL-1β stimulated chondrocytes indicated that PCFMN was biocompatible and upregulated anabolic genes while simultaneously downregulated catabolic genes of the articular cartilage. The therapeutic effects in vivo indicated that PCFMN could effectively attenuate the progression of OA as evidenced by immunohistochemical staining and histological analysis. In addition, PCFMN showed higher intention time in joints and better anti-inflammatory effects than FMN, indicating the efficacy of cartilage targeting nanodrug on OA. This study may provide a reference for clinical OA therapy.

Stimulus-responsive therapy permits precise control of therapeutic effect only at lesion of interest, which determines it a promising method for diagnosis and imaging-guided precision therapy. The acid environment and overexpressed matrix metalloproteinases-13 (MMP-13) are typical markers in osteoarthritis (OA), which enables the development of stimulus-responsive drug delivery system with high specificity for OA. We herein demonstrate a nano-micelle based stimuli-responsive theranostic strategy with reporting and drug release controlled by acidic pH and MMP-13 for OA therapy. Such nanoplatform is incorporated with a motif specifically targeting on cartilage, a motif responsive to matrix metalloproteinases-13 to specifically report OA condition and biodynamics of nano-micelles, an anti-inflammatory drug (e.g., psoralidin (PSO)) from traditional Chinese medicine, and a biocompatible polymeric skeleton for sustainable drug release in response to the acidic OA condition. The high effectiveness of this targeted precision therapy is demonstrated comprehensively by both in vitro and vivo evidences.

Methods that leverage bone marrow mesenchymal stem cells (BMSCs) and stimulating factor kartogenin (KGN) for chondrocyte differentiation have paved the way for cartilage repair. However, the scarce carriers for efficiently bridging the two components significantly impede their further application. Therefore, one kind of bifunctional ferritin has designed and synthesized: RC-Fn, a genetically engineered ferritin nanocage with RGD peptide and WYRGRL peptide on the surface. The RGD can target the integrin αvβ3 of BMSCs and promote proliferation, and the WYRGRL peptide has an inherent affinity for the cartilage matrix component of collagen II protein. RC-Fn nanocages have an ideal size for penetrating the proteoglycan network of cartilage. Thus, intra-articularly injected RC-Fn with KGN loading can convert the articular cavity from a barrier into a reservoir to prevent rapid release and clearance of KGN and exogenous BMSCs, which results in efficient and persistent chondrogenesis in cartilage regeneration.

Low binding affinity and lack of therapy functions limit tumor targeting peptide applications in the biomedical field. Herein, we successfully modified a previous phage display derived Glypican-3 (GPC3) binding peptide (GBP) on the surface of a Fe3O4 Core/Au shell nanocomplex (FANP) to improve GBP binding affinity and enhance FANP tumor photothermal therapy (PTT) efficacy. As a result, GBP-FANP showed improved avidity to GPC-3 (Apparent Kd = 396.3 ± 70.8 nM) compared to that of GPB (Apparent Kd = 735.2 ± 53.6 nM). After intravenous administration, GBP-FANP was found specifically accumulated in GPC-3 positive HepG2 tumors and peaked at 24 h post-injection as observed by magnetic resonance imaging (MRI)/photoacoustic (PA)/fluorescent imaging. Moreover, HepG2 tumors that received GBP-FANP treatment were significantly inhibited with laser irradiation (630 nm, 1 W cm-2, 10 min). In conclusion, our present strategy provides a way of improving peptide ligand avidity with nanotechnology for cancer theranostics applications.

We report the rational design of coordination-driven self-assembly metal-organic nanostructures for multifunctional nanotheranostics. Zinc(II) coordination-based nano-formulations capable of loading indocyanine green (ICG) and therapeutic genes were prepared to achieve a fluorescence/photoacoustic imaging-guided combination photo/gene therapy strategy. We showed the enhanced theranostic capability of zinc(II)-dipicolylamine-assisted assembly of ICG, as well as simultaneous targeted gene delivery in an experimental mouse model of cancer. Such a co-assembly strategy provides a facile way to achieve combined therapeutic functions for personalized nanomedicine.

In vitro expansion of mesenchymal stem cells (MSCs) has been implicated in loss of multipotency, leading to impaired chondrogenic potential and an eventual therapeutic effect, as reported in our previous study. However, the precise regulatory mechanism is still unclear. Here, we demonstrate that endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) were involved in transformation of MSCs induced by in vitro culture based on the comparative profiling of in vitro cultured bone marrow MSCs at passage 3 (P3 BMSCs) vs. fresh P0 BMSCs by microarray analysis. Indeed, RT-PCR and Western blot analysis showed significantly lower expression levels of three key UPR-related molecules, ATF4, ATF6 and XBP1, in P3 BMSCs than P0 BMSCs. Further, we found that UPR suppression by 4-phenylbutyrate (4-PBA) reduced the chondrogenic potential of P0 BMSCs and further cartilage regeneration. Conversely, UPR induction by tunicamycin (TM) enhanced the chondrogenic differentiation of P3 BMSCs and the therapeutic effect on cartilage repair. Thus, the decline in the chondrogenic potential of stem cells after in vitro culture and expansion may be due to changes in ER stress and the UPR pathway.

Intra-articular (IA) injection is an efficient treatment for osteoarthritis. Such a treatment will minimize systemic side effects and avoid the inconvenience of frequent injections. However, the joint has poor bioavailability for systemically administered drugs and experiences rapid clearance of therapeutics after intra-articular injection. Delivering system modified through active targeting strategies to facilitate localization within specific joint tissues such as cartilage is hopeful to increase the therapeutic effects. In this study, we designed a nanoscaled amphiphilic and cartilage-targeting polymer-drug delivery system by using formononetin (FMN)-poly(ethylene glycol) (PEG) (denoted as PCFMN), which was prepared by PEGylation of FMN followed by coupling with cartilage-targeting peptide (CollBP). Our results showed that PCFMN was approximately regular spherical with the average diameter about 218 nm. The in vitro test using IL-1β stimulated chondrocytes indicated that PCFMN were biocompatible and upregulated anabolic genes while simultaneously downregulated catabolic genes of the articular cartilage. The therapeutic effects in vivo indicated that PCFMN could effectively attenuate the progression of OA as evidenced by immunohistochemical staining and histological analysis. In addition, PCFMN showed higher intention time in joints and better anti-inflammatory effects than FMN, indicating the efficacy of cartilage targeting nanodrug on OA. This study may provide reference for clinical OA therapy.

Drug therapy of osteoarthritis (OA) is limited by the short retention and lacking of stimulus-responsiveness after intra-articular (IA) injection. The weak acid microenvironment in joint provides a potential trigger for controlled drug release systems in the treatment of OA. Herein, we developed an pH-responsive metal − organic frameworks (MOFs) system modified by hyaluronic acid (HA) and loaded with an anti-inflammatory protocatechuic acid (PCA), designated as MOF@HA@PCA, for the therapy of OA. Results demonstrated that MOF@HA@PCA could smartly respond to acidic conditions in OA microenvironment and gradually release PCA, which could remarkably reduce synovial inflammation in both IL-1β induced chondrocytes and the OA joints. MOF@HA@PCA also down-regulated the expression of inflammatory markers of OA and promoted the expression of cartilage-specific makers. This work may provide a new insight for the design of efficient nanoprobes for precision theranostics of OA .

Additional file 1: Figure S1. The chemical structures of HA (hyaluronic acid). Figure S2. The chemical structures of PCA (protocatechuic acid). Figure S3. The chemical structures of MOF. Figure S4. The typical chromatogram of PCA. Figure S5. The quantification of Fe3+ by using o-phenanthroline. Figure S6. Degradation study of MOF at different pH. Figure. S7 ROS production induced by MOF after incubation in chondrocytes for 24 h.

Tumor microenvironment-induced ultrasmall nanodrug generation (TMIUSNG) is an unprecedented approach to overcome the drug penetration barriers across complex biological systems, poor circulation stability and limited drug loading efficiency (DLE). Herein, a novel strategy was designed to synthesize metal-organic nanodrug complexes (MONCs) through supramolecular coassembly of photosensitizer sinoporphyrin sodium, chemotherapeutic drug doxorubicin and ferric ions. Compared with the free photosensitizer, MONCs produced 3-fold more reactive oxygen species (ROS) through the energy transfer-mediated fluorescence quenching. Remarkably, the self-delivering supramolecular MONCs with high DLE acted as a potent ultrasmall-nanodrug generator in response to the mild acidic tumor microenvironment to release ultrasmall nanodrugs (5-10 nm in diameter) from larger parental nanoparticles (140 nm in diameter), which in turn enhanced the intratumor permeability and therapeutic efficacy. The key mechanism of MONC synthesis was proposed, and we, for the first time, validated the generation of supramolecular scaffold intermediates between MONCs' assembly/disassembly states, as well as their involvement in multidrug ligands interactions. This proof-of-concept TMIUSNG strategy provides a foundation for the rational design of analogous carrier-free nanotheranostics through the combination of multiple therapeutic agents and metal ions with imaging functions.

Low binding affinity and lack of therapy functions limit tumor targeting peptide applications in the biomedical field. Herein, we successfully modified a previous phage display derived Glypican-3 (GPC3) binding peptide (GBP) on the surface of a Fe

Osteoarthritis (OA) microenvironment is marked by matrix metalloproteinases-13 (MMP-13) overexpression and weak acidity, making it possible to develop dual-stimuli responsive theranostic nanoprobes for OA diagnosis and therapy. However, current MMP/pH-responsive systems are not suitable for OA because of their poor biocompatibility, poor degradation and non-cartilage-targeting of the responsive probes. Here we designed a novel biocompatible cartilage-targeting and MMP-13/pH-responsive ferritin nanocages (CMFn) loaded with an anti-inflammatory drug (Hydroxychloroquine, HCQ), termed CMFn@HCQ, for OA imaging and therapy. We found that CMFn could be smartly "turned on" to emit light for OA imaging in response to the level of overexpressed MMP-13 in OA microenvironment, corresponding to the degree of OA severity. Thus the light intensity detected reflected the degree of OA severity, enabling the precise disease classification by our CMFn. CMFn could be "turned off" to stop emitting light in the normal joint. CMFn@HCQ nanocages could target the cartilage and release HCQ in the OA joint specifically under acidic pH conditions in a sustained manner, prolonging the drug retention time to 14 days to remarkably reduce synovial inflammation in the OA joints. The CMFn@HCQ nanocages represent a smart dual-stimuli responsive and cartilage-targeting nanoprobes, and hold promise for imaging-guided precision therapy for OA.

Directed differentiation of bone‐marrow‐derived stem cells (BMSCs) toward chondrogenesis has served as a predominant method for cartilage repair but suffers from poor oriented differentiation tendency and low differentiation efficiency. To overcome these two obstacles, an injectable composite hydrogel that consists of collagen hydrogels serving as the scaffold support to accommodate BMSCs and cadmium selenide (CdSe) quantum dots (QDs) is constructed. The introduction of CdSe QDs considerably strengthens the stiffness of the collagen hydrogels via mutual crosslinking using a natural crosslinker (i.e., genipin), which simultaneously triggers photodynamic provocation (PDP) to produce reactive oxygen species (ROS). Experimental results demonstrate that the intensified stiffness and augmented ROS production can synergistically promote the proliferation of BMSCs, induce cartilage‐specific gene expression and increase secretion of glycosaminoglycan. As a result, this approach can facilitate the directed differentiation of BMSCs toward chondrogenesis and accelerate cartilage regeneration in cartilage defect repair, which routes through activation of the TGF‐β/SMAD and mTOR signaling pathways, respectively. Thus, this synergistic strategy based on increased stiffness and PDP‐mediated ROS production provides a general and instructive approach for developing alternative materials applicable for cartilage repair.

Intra-articular (IA) drug delivery to treat osteoarthritis (OA) is limited by the short retention time of drugs in the joints due to poor specific targeting and non-responsiveness under acidic environment. A cartilage-targeting peptide was engineered to the surface of ferritin nanocages (CT-Fn) and loaded with an anti-inflammatory drug, metformin (Met), via the self-assembling nature of Fn nanocages. It demonstrated that the CT-Fn/Met could specifically bind to type II collagen, leading to the downregulation of catabolic markers of OA and promotion of cartilage-specific makers in IL-1β-induced chondrocytes. IA delivery of CT-Fn/Met prolonged the retention time for 3 weeks and remarkably reduced inflammation. Moreover, better release under acidic conditions which enabling longer retention time of Met after IA delivery in OA joints for one more week. CT-Fn/Met could target and efficiently enter chondrocytes, further inducing prolonged IA accumulation and achieving enhanced therapeutic efficacy for OA treatment.

Chemotherapy is a standard care for cancer management, but the lack of tumor targeting and high dose-induced side effects still limit its utility in patients. Here, we report a chemotherapy combined with photothermal therapy (PTT) for enhanced cancer ablation by functionalization of gold nanorods (GNRs) with a novel small molecule named truncated Evans blue (tEB). On the basis of the high binding affinity of tEB with albumin, an Abraxane-like nanodrug, human serum albumin/hydroxycamptothecin (HSA/HCPT), was further complexed with GNR-tEB. This formed an HCPT/HSA/tEB-GNR (HHEG) with excellent biostability and biocompatibility. With photoacoustic and fluorescence imaging, we observed HHEG tumor targeting, which is mediated by enhanced permeability retention effect. The accumulation of HHEG peaked in tumor at 12 h postinjection. Moreover, HHEG can effectively ablate tumor growth with laser illumination via chemo/thermal therapy after intravenous administration into SCC7 tumor. This combination is much better than chemotherapy or PTT alone. Collectively, we constructed a chemo/thermal therapy nanostructure based on a tEB-modified GNR for better tumor treatment effect. The use of tEB in gold nanoparticles can facilitate many new approaches to design hybrid nanoparticles.

In vitro expansion of mesenchymal stem cells (MSCs) has been implicated in loss of multipotency, leading to impaired chondrogenic potential and eventually therapeutic effect, as reported in our previous study. However, the precise regulatory mechanism is still unclear. Here, we demonstrate that endoplasmic reticulum (ER) stress and unfolded protein response (UPR) were highly enriched in in vitro-cultured bone marrow MSCs at passage 3 (P3 BMSCs) vs. flesh P0 BMSCs by microarray analysis. Indeed, RT-PCR and western blot analysis showed significantly lower expression levels of three key UPR-related molecules, ATF4, ATF6 and XBP1 in P3 BMSCs than P0 BMSCs. Further, we found that UPR suppression by 4-phenylbutyrate (4-PBA) impaired chondrogenesis and cartilage repair in P0 BMSCs, and UPR induction by tunicamycin (TM) enhanced chondrogenic differentiation and cartilage regeneration in in vitro-cultured P3 BMSCs. Thus, the decline of chondrogenic potential of stem cells after in vitro culture and expansion may be due to the change of ER stress and UPR pathway. Funding: This study was financially supported by National key research and development program of China (2016YFB0700804), National Natural Science Fund of China (Grant No. 81760326 and 81460345), the Guangxi Scientific Research and Technological Development Foundation (Grant No. GuikeAB16450003) and the Guangxi Science and Technology Major Project (Guike AA17204085), High level innovation teams and outstanding scholars in Guangxi Universities (The third batch), the Distinguished Young Scholars Program of Guangxi Medical University, and the Key scientific research collaboration program of Guangxi Biomedical Collaborative Innovation Center (GCICB-SR-2017002). Declaration of Interest: No conflict of interests exists in this study. Ethical Approval: The experiments were approved by Animal Care and Experiment Committee of Guangxi Medical University (protocol number: 2014-12-3).

Ligand-targeted delivery of drug molecules to various types of tumor cells remains a major challenge in precision medicine. Inspired by the secretion process and natural cargo delivery functions of natural exosomes, biomimetic synthetic strategies are exploited to prepare biofunctionalized liposome-like nanovesicles (BLNs) that can artificially display a wide variety of targeting protein/peptide ligands and directly encapsulate medical agents for enhanced drug delivery. Here, as a proof of concept, genetically engineered BLNs, which display human epidermal growth factor (hEGF) or anti-HER2 Affibody as targeting moieties, are developed to, respectively, target two types of tumor cells. Notably, in comparison to synthetic liposomes covalently coupled with hEGF, it is demonstrated in this work that biosynthetically displayed hEGF ligands on BLNs possess higher biological activities and targeting capabilities. Additionally, treatments with doxorubicin-loaded BLNs displaying Affibody ligands exhibit much better antitumor therapeutic outcomes than clinically approved liposomal doxorubicin (Doxil) in HER2-overexpressing BT474 tumor xenograft models. These data suggest that BLN is suitable as a potent surrogate for conventional proteoliposomes or immunoliposomes as a result of excellent targeting capacities and facile production of BLNs.

The delivery of therapeutic cancer agents via nanomaterials has attracted great attention recently. Although encouraging, tumor treatment response remains unsatisfactory. To address this concern, we constructed a new micellar nanocomplex by conjugating hyaluronic acid (HA) with iron oxide nanoparticle (IONP). When an external magnetic field is applied to the tumor area, HA-IONP will specifically accumulate in the tumor due to the strong IONP magnetism. In addition, HA can bind to CD44 that is overexpressed on tumor cells. With combined magnetic, CD44, and EPR targeting, the efficient delivery of HA-IONP into the tumor is expected to enhance cancer treatment efficiency. After encapsulation of the chemotherapy drug, homocamptothecin (HCPT), the theranostic potency of HA-IONP/HCPT (HIH), was investigated. The improved tumor homing behavior of HIH was observed by magnetic resonance imaging (MRI) when an external magnetic field is utilized. Moreover, HIH showed remarkable tumor ablation efficiency with magnetic targeting after 3 mg/kg intravenous administration (equivalent dose of free HCPT), and the tumors almost disappeared after treatment. No obvious systemic toxicity was detected. This excellent biocompatibility and tumor targetability suggests that HIH is a promising theranostic nanocomplex with great translational potency. The application of HA-IONP platform can also be extended to delivery of the other hydrophobic chemotherapy drugs or phototherapy agents.

Collagen has been widely used for cartilage repair, but its low stiffness and rapid degradation disfavor chondrogenesis. Here we conjugated biocompatible carbon dot nanoparticles (CD NPs) onto collagen through a natural product crosslinker (genipin) to prepare an injectable hydrogel (termed collagen-genipin-CD nanoparticles, CGN). The CGN hydrogel showed increased stiffness due to the cross-linking effect of genipin and the presence of CD NPs, and could produce a moderate amount of reactive oxygen species (ROS) by photodynamic therapy (PDT). Both the stiffness enhancement and ROS generation resulted in improved chondrogenic differentiation of bone marrow-derived stem cells (BMSCs) and the subsequent enhanced cartilage regeneration for cartilage defect repair. Specifically, the CGN hydrogel presented a 21-fold higher compression modulus and a 39.3% lower degradation rate than the pure collagen hydrogel. A combination of both PDT and CGN hydrogel increased the BMSCs proliferation by 50.3%, upregulated their expression of cartilage-specific genes by multiple folds, and enhanced GAG secretion by 205.1% on day 21. This combination also accelerated the cartilage regeneration within as short as 8 weeks. The stiffness enhancement and ROS generation synergistically contributed to chondrogenic differentiation by regulating the TGF-β/SMAD and mTOR signaling pathway, respectively. The combination of CD-modified hydrogel injection and PDT treatment represents a new strategy for minimally invasive repair of cartilage defects.

Early and accurate detection of hepatocellular carcinoma (HCC) is essential to improve the prognosis of patients and reduce the morbidity of surgical therapy. Glypican-3 (GPC3) is a protein abnormally expressed in HCC that has been identified as a serological and histochemical HCC marker. A novel peptide that specifically recognizes GPC3 will facilitate early detection of HCC and guide the treatment strategy. Herein, phage display screening technology is utilized to obtain a GPC3 binding peptide (GBP) using HCC cells expressing GPC3 in varying abundances. After seven rounds of panning, a peptide with sequence of THVSPNQGGLPS is identified with 735.2 ± 53.6 × 10−9 m affinity to GPC3. The ability to target GPC3 in vivo is evaluated by intravenous injection of GBP labeled with a near-infrared dye, Cy5.5, into a HCC tumor-bearing mouse model. Significant high tumor accumulation (tumor/muscle ratio: 6.49 ± 0.55) of Cy5.5-GBP in HepG2 tumors is observed compared with that of the low GPC3 expressing prostate cancer cell line, PC3 (tumor/muscle ratio: 1.15 ± 0.32). By targeting GPC3, GBP differentiates tumor tissues from normal liver tissues in patients, suggesting a great clinical translation potency of GBP. Collectively, GBP demonstrates great potential for HCC detection via fluorescent imaging or histological staining.