Carrier-free Nanoparticles Research Articles

Tailoring Carrier-Free Nanoparticles based on Natural Small Molecule Assembly for Synergistic Anti-tumor Efficacy

Tailoring Carrier-Free Nanoparticles based on Natural Small Molecule Assembly for Synergistic Anti-tumor Efficacy

Targeted no-releasing L-arginine-induced hesperetin self-assembled nanoparticles for ulcerative colitis intervention

Overproduction of reactive oxygen species (ROS) plays a crucial role in initiating and advancing ulcerative colitis (UC), and the persistent cycle between ROS and inflammation accelerates disease development. Therefore, developing strategies that can effectively scavenge ROS and provide targeted intervention are crucial for the management of UC. In this study, we synthesized natural carrier-free nanoparticles (HST-Arg NPs) using the Mannich reaction and π-π stacking for the intervention of UC. HST-Arg NPs are an oral formulation that exhibit good antioxidant capabilities and gastrointestinal stability. Benefiting from the negatively charged characteristics, HST-Arg NPs can specifically accumulate in positively charged inflamed regions of the colon. Furthermore, in the oxidative microenvironment of colonic inflammation, HST-Arg NPs respond to ROS by releasing nitric oxide (NO). In mice model of UC induced by dextran sulfate sodium (DSS), HST-Arg NPs significantly mitigated colonic injury by modulating oxidative stress, lowering pro-inflammatory cytokines, and repairing intestinal barrier integrity. In summary, this convenient and targeted oral nanoparticle can effectively scavenge ROS at the site of inflammation and achieve gas intervention, offering robust theoretical support for the development of subsequent oral formulations in related inflammatory interventions. Statement of significanceNanotechnology has been extensively explored in the biomedical field, but the application of natural carrier-free nanotechnology in this area remains relatively rare. In this study, we developed a natural nanoparticle system based on hesperetin (HST), L-arginine (L-Arg), and vanillin (VA) to scavenge ROS and alleviate inflammation. In the context of ulcerative colitis (UC), the synthesized nanoparticles exhibited excellent intervention effects, effectively protecting the colon from damage. Consequently, these nanoparticles provide a promising and precise nutritional intervention strategy by addressing both oxidative stress and inflammatory pathways simultaneously, demonstrating significant potential for application.

Carrier-free nanoparticles based on self-assembly of 5-FU and copper-genistein complexes for the combined treatment of hepatocellular carcinoma.

5-Fluorouracil (5-FU) is commonly used as a chemotherapeutic drug for advanced HCC. However, the effectiveness of 5-FU is limited by the emergence of resistance and poor targeting efficiency. Combining 5-FU with natural compounds has shown promise in HCC treatment. In this study, we prepared carrier-free nanoparticles (GEN-Cu-GEN@FUA) containing 5-FU and genistein (GEN) in a synergistic ratio via a green synthesis procedure. The resulting GEN-Cu-GEN@FUA nanoparticles had a spherical or near spherical shape, a dynamic size of 129.3 ± 40.1nm, and a high drug loading content of approximately 21.40% (5-FU) and 61.48% (GEN). These nanoparticles exhibited approximately 3.6-fold lower IC50 value than 5-FU alone in Bel-7402 cells and resulted in a 3.7-fold greater reduction in tumor weight compared to 5-FU alone in Bel-7402 tumor-bearing BALB/c mice. Importantly, the nanoparticles showed negligible systemic toxicity due to their synergistic effect on cancer cell dysfunction and significant amplification of intracellular glutathione consumption. Our findings suggest that the developed carrier-free nanomedicines offer a highly promising platform for the co-delivery of genistein (GEN) copper(II) complexes and 5-FU, with easy fabrication and great potential for clinical translation in HCC synergistic therapy.

Self-assembly of a ruthenium-based cGAS-STING photoactivator for carrier-free cancer immunotherapy

The cGAS (cyclic GMP-AMP synthase)-STING (stimulator of interferon genes) pathway promotes antitumor immune responses by sensing cytosolic DNA fragments leaked from nucleus and mitochondria. Herein, we designed a highly charged ruthenium photosensitizer (Ru1) with a β-carboline alkaloid derivative as the ligand for photo-activating of the cGAS-STING pathway. Due to the formation of multiple non-covalent intermolecular interactions, Ru1 can self-assemble into carrier-free nanoparticles (NPs). By incorporating the triphenylphosphine substituents, Ru1 can target and photo-damage mitochondrial DNA (mtDNA) to cause the cytoplasmic DNA leakage to activate the cGAS-STING pathway. Finally, Ru1 NPs show potent antitumor effects and elicit intense immune responses in vivo. In conclusion, we report the first self-assembling mtDNA-targeted photosensitizer, which can effectively activate the cGAS-STING pathway, thus providing innovations for the design of new photo-immunotherapeutic agents.

Dual depletion of myeloid-derived suppressor cells and tumor cells with self-assembled gemcitabine-celecoxib nano-twin drug for cancer chemoimmunotherapy

Myeloid-derived suppressor cells (MDSCs) have played a significant role in facilitating tumor immune escape and inducing an immunosuppressive tumor microenvironment. Eliminating MDSCs and tumor cells remains a major challenge in cancer immunotherapy. A novel approach has been developed using gemcitabine-celecoxib twin drug-based nano-assembled carrier-free nanoparticles (GEM-CXB NPs) for dual depletion of MDSCs and tumor cells in breast cancer chemoimmunotherapy. The GEM-CXB NPs exhibit prolonged blood circulation, leading to the preferential accumulation and co-release of GEM and CXB in tumors. This promotes synergistic chemotherapeutic activity by the proliferation inhibition and apoptosis induction against 4T1 tumor cells. In addition, it enhances tumor immunogenicity by immunogenic cell death induction and MDSC-induced immunosuppression alleviation through the depletion of MDSCs. These mechanisms synergistically activate the antitumor immune function of cytotoxic T cells and natural killer cells, inhibit the proliferation of regulatory T cells, and promote the M2 to M1 phenotype repolarization of tumor-associated macrophages, considerably enhancing the overall antitumor and anti-metastasis efficacy in BALB/c mice bearing 4T1 tumors. The simplified engineering of GEM-CXB NPs, with their dual depletion strategy targeting immunosuppressive cells and tumor cells, represents an advanced concept in cancer chemoimmunotherapy.Graphical

Carrier-Free Self-Assembly Nano-Sonosensitizers for Sonodynamic-Amplified Cuproptosis-Ferroptosis in Glioblastoma Therapy.

Cuproptosis is a newly discovered form of programmed cell death significantly depending on the transport efficacy of copper (Cu) ionophores. However, existing Cu ionophores, primarily small molecules with a short blood half-life, face challenges in transporting enough amounts of Cu ions into tumor cells. This work describes the construction of carrier-free nanoparticles (Ce6@Cu NPs), which self-assembled by the coordination of Cu2+ with the sonosensitizer chlorin e6 (Ce6), facilitating sonodynamic-triggered combination of cuproptosis and ferroptosis. Ce6@Cu NPs internalized by U87MG cells induce a sonodynamic effect and glutathione (GSH) depletion capability, promoting lipid peroxidation and eventually inducing ferroptosis. Furthermore, Cu+ concentration in tumor cells significantly increases as Cu2+ reacts with reductive GSH, resulting in the downregulation of ferredoxin-1 and lipoyl synthase. This induces the oligomerization of lipoylated dihydrolipoamide S-acetyltransferase, causing proteotoxic stress and irreversible cuproptosis. Ce6@Cu NPs possess a satisfactory ability to penetrate the blood-brain barrier, resulting in significant accumulation in orthotopic U87MG-Luc glioblastoma. The sonodynamic-triggered combination of ferroptosis and cuproptosis in the tumor by Ce6@Cu NPs is evidenced both in vitro and in vivo with minimal side effects. This work represents a promising tumor therapeutic strategy combining ferroptosis and cuproptosis, potentially inspiring further research in developing logical and effective cancer therapies based on cuproptosis.

Design and development of novel self-assembled catechol-modified bile acid conjugates as pH-responsive apical sodium-dependent bile acid transporter targeting nanoparticles

Catechol-based biomaterials demonstrate biocompatibility, making them suitable for a wide range of therapeutic applications when integrated into various molecular frameworks. However, the development of orally available catechol-based biomaterials has been hindered by significant pH variations and complex interactions in the gastrointestinal (GI) tract. In this study, we introduce a novel catechol-modified bile acid (CMBA), which is synthesized by anchoring the FDA-approved drug, ursodeoxycholic acid to the neurotransmitter dopamine. This modification could form a new apical sodium-dependent bile acid transporter (ASBT) inhibitor (ASBTi) due to the bile acid moiety. The computational analysis using the TRAnsient Pockets in Proteins (TRAPP) module, coupled with MD simulations, revealed that CMBA exhibits a strong binding affinity at residues 51–55 of ASBT with a low inhibitory constant (Ki) value. Notably, in slightly alkaline biological conditions, CMBA molecules self-assemble into carrier-free nanoparticles with an average size of 240.2 ± 44.2 nm, while maintaining their ability to bind with ASBT. When administered orally, CMBA accumulates in the ileum and liver over 24 h, exhibiting significant therapeutic effects on bile acid (BA) metabolism in a high-fat diet (HFD)-fed mouse model. This study underscores the therapeutic potential of the newly developed catechol-based, pH-responsive ASBT-inhibiting nanoparticles presenting a promising avenue for advancing therapy.

PH-Responsive Carrier-Free Polyphenol Nanoparticles Assembled by Oxidative Polymerization with Enhanced Stability and Antioxidant Activity for Improved Bioaccessibility.

Encapsulation of plant polyphenols with micro-/nano-carriers for enhanced bioavailability has been well documented, but the preparation of these carriers and subsequent loading of polyphenols is a multiple process, which is generally complicated with potentially unexpected negative effects on the bioactivity of the polyphenols. Here, we reported a convenient method to assemble carrier-free polyphenol nanoparticles (NPs) based on oxidative coupling polymerization. The effectiveness was assessed with five different polyphenols including pyrocatechol (PY), catechin (CA), epigallocatechin gallate (EGCG), tannic acid (TA), and proanthocyanidin (PC). The structural characteristics of these assembled nanoparticles (PY NPs, CA NPs, EG NPs, TA NPs, and PC NPs) were systematically analyzed with dynamic light scattering (DLS), transmission electron microscopy (TEM), UV-visible spectroscopy, and Fourier transform infrared spectroscopy (FTIR). All NPs were colloidally stable with varying NaCl concentrations from 0 to 300 mM, were acid-resistant and alkali-intolerant, and were suitable for oral administration. An array of antioxidant assays further confirmed the superior antioxidant capabilities of NPs over Trolox and polyphenol monomers, indicating that the oxidative polymerization of polyphenols did not compromise the polyphenol activity of NPs. The in vitro simulated digestion studies validated that these responsive NPs were actually gastrointestinal pH-responsive and applicable to the gastrointestinal physiological environment. The bioaccessibility assessments by using a static in vitro digestion model revealed that better results were achieved with NPs than polyphenol monomers, with TA NPs showing about 1.5-fold higher bioaccessibility than other polyphenol nanoparticles. The present study with five polyphenols demonstrated that the oxidative polymerization of polyphenols provides an effective platform to assemble various carrier-free NPs with enhanced antioxidant activity, favorable stability, and improved bioaccessibility, which could be used promisingly as a functional food ingredient in food matrices or as oral drug delivery candidates for helping to manage human health or treating various gastrointestinal disorders in both the pharmaceutical and nutritional fields.

Morusin-Cu(II)-indocyanine green nanoassembly ignites mitochondrial dysfunction for chemo-photothermal tumor therapy

Nanoscale drug delivery systems derived from natural bioactive materials accelerate the innovation and evolution of cancer treatment modalities. Morusin (Mor) is a prenylated flavonoid compound with high cancer chemoprevention activity, however, the poor water solubility, low active pharmaceutical ingredient (API) loading content, and instability compromise its bioavailability and therapeutic effectiveness. Herein, a full-API carrier-free nanoparticle is developed based on the self-assembly of indocyanine green (ICG), copper ions (Cu2+) and Mor, termed as IMCNs, via coordination-driven and π-π stacking for synergistic tumor therapy. The IMCNs exhibits a desirable loading content of Mor (58.7 %) and pH/glutathione (GSH)-responsive motif. Moreover, the photothermal stability and photo-heat conversion efficiency (42.8 %) of IMCNs are improved after coordination with Cu2+ and help to achieve photothermal therapy. Afterward, the released Cu2+ depletes intracellular overexpressed GSH and mediates Fenton-like reactions, and further synergizes with ICG at high temperatures to expand oxidative damage. Furthermore, the released Mor elicits cytoplasmic vacuolation, expedites mitochondrial dysfunction, and exerts chemo-photothermal therapy after being combined with ICG to suppress the migration of residual live tumor cells. In vivo experiments demonstrate that IMCNs under laser irradiation could excellently inhibit tumor growth (89.6 %) through the multi-modal therapeutic performance of self-enhanced chemotherapy/coordinated-drugs/ photothermal therapy (PTT), presenting a great potential for cancer therapy.

Bilirubin/morin self-assembled nanoparticle-engulfed collagen/polyvinyl alcohol hydrogel accelerates chronic diabetic wound healing by modulating inflammation and ameliorating oxidative stress

Chronic diabetic wounds pose a serious threat to human health and safety because of their refractory nature and high recurrence rates. The formation of refractory wounds is associated with wound microenvironmental factors such as increased expression of proinflammatory factors and oxidative stress. Bilirubin is a potent endogenous antioxidant, and morin is a naturally active substance that possesses anti-inflammatory and antioxidant effects. Both hold the potential for diabetic wound treatment by intervening in pathological processes. In this study, we developed bilirubin/morin-based carrier-free nanoparticles (BMn) to treat chronic diabetic wounds. In vitro studies showed that BMn could effectively scavenge overproduced reactive oxygen species and suppress elevated inflammation, thereby exerting a protective effect. BMn was then loaded into a collagen/polyvinyl alcohol gel (BMn@G) for an in vivo study to maintain a moist environment for the skin and convenient biomedical applications. BMn@G exhibits excellent mechanical properties, water retention capabilities, and in vivo safety. In type I diabetic mice, BMn@G elevated the expression of the anti-inflammatory factor IL-10 and concurrently diminished the expression of the proinflammatory factor TNF-α in the tissues surrounding the wounds. Furthermore, BMn@G efficiently mediated macrophage polarization from the M1-type to the M2-type, thereby fostering anti-inflammatory effects. Additionally, BMn@G facilitated the conversion of type III collagen fiber bundles to type I collagen fiber bundles, resulting in a more mature collagen fiber structure. This study provides a promising therapeutic alternative for diabetic wound healing.

Mitochondria-targeted carrier-free nanoparticles based on dihydroartemisinin against hepatocellular carcinoma

Hepatocellular carcinoma is a common and fatal malignancy for which there is no effective systemic therapeutic strategy. Dihydroartemisinin (DHA), a derivative of artemisinin, has been shown to exert anti-tumor effects through the production of reactive oxygen species (ROS) and resultant mitochondrial damage. However, clinical translation is limited by several drawbacks, such as insolubility, instability and low bioavailability. Here, based on a nanomedicine-based delivery strategy, we fabricated mitochondria-targeted carrier-free nanoparticles coupling DHA and triphenylphosphonium (TPP), aiming to improve bioavailability and mitochondrial targeting. DHA-TPP nanoparticles can be passively delivered to the tumor site by enhanced penetration and retention and then internalized. Flow cytometry and Western blot analysis showed that DHA-TPP nanoparticles increased intracellular ROS, which increased mitochondrial stress and in turn upregulated the downstream Bcl-2 pathway, leading to apoptosis. In vivo experiments showed that DHA-TPP nanoparticles exhibited anti-tumor effects in a mouse model of hepatocellular carcinoma. These findings suggest carrier-free DHA-TPP nanoparticles as a potential therapeutic strategy for hepatocellular carcinoma.

An innovative gene expression modulating strategy by converting nucleic acids into HNC therapeutics using carrier-free nanoparticles.

Cell fate and microenvironmental changes resulting from aberrant expression of specific proteins in tumors are one of the major causes of inadequate anti-tumor immune response and poor prognosis in head and neck cancer (HNC). Eukaryotic initiation factor 3C (eIF3c) has emerged as a promising therapeutic target for HNC due to its ability to regulate protein expression levels in tumor cells, but its drug development is difficult to achieve by targeting traditional protein-protein interactions. siRNA has emerged as a highly promising modality for drug development targeting eIF3c, while its application is hindered by challenges pertaining to inadequate stability and insufficient concentration specifically within tumor sites. We employed a method to convert flexible siRNAs into stable and biologically active infinite Auric-sulfhydryl coordination supramolecular siRNAs (IacsRNAs). Through coordinated self-assembly, we successfully transformed eIF3C siRNAs into the carrier-free HNC nanotherapeutic agent Iacs-eif3c-RNA. The efficacy of this agent was evaluated in vivo using HNC xenograft models, demonstrating promising antitumor effects. Iacs-eif3c-RNA demonstrated the ability to overcome the pharmacological obstacle associated with targeting eIF3C, resulting in a significant reduction in eIF3C expression within tumor tissues, as well as effective tumor cell proliferating suppression and apoptosis promotion. In comparison to monotherapy utilizing the chemotherapeutic agent cisplatin, Iacs-eif3c-RNA exhibited superior anti-tumor efficacy and favorable biosafety. The utilization of Iacs-eif3c-RNA as a carrier-free nanotherapeutic agent presents a promising and innovative approach for addressing HNC treating challenges. Moreover, this strategy demonstrates potential for the translation of therapeutic siRNAs into clinical drugs, extending its applicability to the treatment of other cancers and various diseases.

Sonodynamic-chemotherapy synergy with chlorin e6-based carrier-free nanoparticles for non-small cell lung cancer.

Sonodynamic therapy (SDT), an emerging cancer treatment with significant potential, offers the advantages of non-invasiveness and deep tissue penetrability. The method involves activating sonosensitizers with ultrasound to generate reactive oxygen species (ROS) capable of eradicating cancer cells, addressing the challenge faced by photodynamic therapy (PDT) where conventional light sources struggle to penetrate deep tissues, impacting treatment efficacy. This study addresses prevalent challenges in numerous nanodiagnostic and therapeutic agents, such as intricate synthesis, poor repeatability, low stability, and high cost, by introducing a streamlined one-step assembly method for nanoparticle preparation. Specifically, the sonosensitizer Chlorin e6 (Ce6) and the chemotherapy drug erlotinib are effortlessly combined and self-assembled under sonication, yielding carrier-free nanoparticles (EC-NPs) for non-small cell lung cancer (NSCLC) treatment. The resulting EC-NPs exhibit optimal drug loading capacity, a simplified preparation process, and robust stability both in vitro and in vivo, owing to their carrier-free characteristics. Under the synergistic treatment of sonodynamic therapy and chemotherapy, EC-NPs induce an excess of reactive oxygen in tumor tissue, prompting apoptosis of cancer cells and reducing their proliferative capacity. Both in vitro and in vivo experiments demonstrate superior therapeutic effects of EC-NPs under ultrasound conditions compared to free Ce6. In summary, our research findings highlight that the innovatively designed carrier-free sonosensitizer EC-NPs present a therapeutic option with commendable efficacy and minimal side effects.

Hypoxia-Responsive Golgi-Targeted Prodrug Assembled with Anthracycline for Improved Antitumor and Antimetastasis Efficacy.

Tumor metastasis is an intricate multistep process regulated via various proteins and enzymes modified and secreted by swollen Golgi apparatus in tumor cells. Thus, Golgi complex is considered as an important target for the remedy of metastasis. Currently, Golgi targeting technologies are mostly employed in Golgi-specific fluorescent probes for diagnosis, but their applications in therapy are rarely reported. Herein, we proposed a prodrug (INR) that can target and destroy the Golgi apparatus, which consisted of indomethacin (IMC) as the Golgi targeting moiety and retinoic acid (RA), a Golgi disrupting agent. The linker between IMC and RA was designed as a hypoxia-responsive nitroaromatic structure, which ensured the release of the prototype drugs in the hypoxic tumor microenvironment. Furthermore, INR could be assembled with pirarubicin (THP), an anthracycline, to form a carrier-free nanoparticle (NP) by emulsion-solvent evaporation method. A small amount of mPEG2000-DSPE was added to shield the positive charges and improve the stability of the nanoparticle to obtain PEG-modified nanoparticle (PNP). It was proved that INR released the prototype drugs in tumor cells and hypoxia promoted the release. The Golgi destructive effect of RA in INR was amplified owing to the Golgi targeting ability of IMC, and IMC also inhibited the protumor COX-2/PGE2 signaling. Finally, PNP exhibited excellent curative efficacy on 4T1 primary tumor and its pulmonary and hepatic metastasis. The small molecular therapeutic prodrug targeting Golgi apparatus could be adapted to multifarious drug delivery systems and disease models, which expanded the application of Golgi targeting tactics in disease treatment.

Carrier-Free Gambogic Acid Dimer Self-Assembly Nanomedicines for Rheumatoid Arthritis Treatment.

The insufficient targeting delivery of therapeutic agents greatly impeded the treatment outcomes of rheumatoid arthritis (RA). Despite the recognized therapeutic advantages of gambogic acid (GBA) in inflammatory diseases, its high delivery efficiency to inflammatory site still limits its clinical application. Self-assembly of drug dimers into carrier-free nanoparticles (NPs) has become a straightforward and attractive approach to develop nanomedicines for RA treatment. Herein, homodimers of GBA were designed to form the carrier-free NPs by self-assembly for RA treatment. The synthetic gambogic acid dimers (GBA2) were self-assembled into NPs using a one-step solvent evaporation method. The size distribution, morphology, drug-loading efficiency (DLE) and storage stability were evaluated. A molecular dynamic simulation was conducted to gain further insight into the self-assembly mechanisms of GBA2/NPs. Besides, we investigated the cytotoxicity, apoptosis and cellular uptake profiles of GBA2/NPs in macrophages and osteoclasts. Finally, the specific biodistribution on the ankles of adjuvant-induced arthritis (AIA) mice, and the anti-RA efficacy of the AIA rat model were assessed. GBA2/NPs exhibited the uniform spherical structure, possessing excellent colloidal stability, high self-assembly stability, high drug loading and low hemolytic activity. Comparing with GBA, GBA2/NPs showed higher cytotoxicity, cellular uptake and apoptosis rate against osteoclasts. In addition, GBA2/NPs exhibited much higher accumulation in ankle joints in vivo. As expected, the systematic administration of GBA2/NPs resulted in the greater alleviation of arthritic symptoms, cartilage protection, and inflammation, notably the reduced systemic toxicity compared to free GBA. GBA2/NPs formed GBA dimers exhibited the superior accumulation in the inflamed joint and anti-RA activity, potentially attributing to the similar extravasation through leaky vasculature and subsequent inflammatory cell-mediated sequestration ("ELVIS") effects in inflamed joint and the enhanced cellular uptake in macrophages and osteoclasts. Our findings provide substantial evidence that self-assembly of GBA2/NPs would be a promising therapeutic alternative for RA treatment.

A multifunctional integrated biomimetic spore nanoplatform for successively overcoming oral biological barriers

The biological barriers have seriously restricted the efficacious responses of oral delivery system in diseases treatment. Utilizing a carrier based on the single construction means is hard to overcome these obstacles simultaneously because the complex gastrointestinal tract environment requires carrier to have different or even contradictory properties. Interestingly, spore capsid (SC) integrates many unique biological characteristics, such as high resistance, good stability etc. This fact offers a boundless source of inspiration for the construction of multi-functional oral nanoplatform based on SC without further modification. Herein, we develop a type of biomimetic spore nanoplatform (SC@DS NPs) to successively overcome oral biological barriers. Firstly, doxorubicin (DOX) and sorafenib (SOR) are self-assembled to form carrier-free nanoparticles (DS NPs). Subsequently, SC is effectively separated from probiotic spores and served as a functional vehicle for delivering DS NPs. As expect, SC@DS NPs can efficaciously pass through the rugged stomach environment after oral administration and further be transported to the intestine. Surprisingly, we find that SC@DS NPs exhibit a significant improvement in the aspects of mucus penetration and transepithelial transport, which is related to the protein species of SC. This study demonstrates that SC@DS NPs can efficiently overcome multiple biological barriers and improve the therapeutic effect.

CDK4/6 nano-PROTAC enhances mitochondria-dependent photodynamic therapy and anti-tumor immunity

Cell cycle progression in cancer cells is highly activated, making CDK4/6 inhibition-based cell cycle arrest a potent cancer treatment strategy. To enhance therapeutic efficacy, it is crucial to explore CDK4/6 inhibition-based combination strategies. In this study, we found that combing CDK4/6 PROTAC with Chlorin e6-based photodynamic therapy produced a synergistic anti-cancer effect. This combination effect was mediated by mitochondria accumulation and activation, leading to increased production of reactive oxygen species and apoptosis. To promote clinical translation, we developed a self-assembled, carrier-free nanoparticle system to co-deliver these two molecules. The dual-drug nanoparticles not only induced higher apoptosis but also cooperatively induced immunogenic cell death and chemotaxis of immune cells, remodulating immunosuppressive tumor microenvironment to enhance anti-tumor immunity. This study provides a promising strategy to combine G1 cell cycle blockage and photodynamic therapy and advances the broad applications of PROTAC in clinical cancer treatment.

Unadulterated BODIPY nanoparticles as light driven antibacterial agents for treating bacterial infections and promoting wound healing.

Antimicrobial photodynamic therapy (aPDT) is an effective strategy to eliminate bacteria without inducing bacterial resistance. As typical aPDT photosensitizers, most of boron-dipyrromethene (BODIPY) are hydrophobic, and nanometerization is imperative to render them dispersible in physiological media. Recently, carrier-free nanoparticles (NPs) are formed via the self-assembly of BODIPYs without the help of any surfactants or auxiliaries, arousing people's interest. So as to fabricate carrier-free NPs, BODIPYs usually need to be derived into dimers, trimers, or amphiphiles through complex reactions. Few unadulterated NPs were obtained from BODIPYs with precise structures. Herein, BNP1-BNP3 were synthesized by the self-assembly of BODIPY, which showed excellent anti-Staphylococcus aureus ability. Among them, BNP2 could effectively fight bacterial infections and promote wound healing in vivo.

NIR-responsive carrier-free nanoparticles based on berberine hydrochloride and indocyanine green for synergistic antibacterial therapy and promoting infected wound healing.

Bacterial infections cause severe health conditions, resulting in a significant economic burden for the public health system. Although natural phytochemicals are considered promising anti-bacterial agents, they suffer from several limitations, such as poor water solubility and low bioavailability in vivo, severely restricting their wide application. Herein, we constructed a near-infrared (NIR)-responsive carrier-free berberine hydrochloride (BH, phytochemicals)/indocyanine green (ICG, photosensitizer) nanoparticles (BI NPs) for synergistic antibacterial of an infected wound. Through electrostatic interaction and π-π stacking, the hydrophobic BH and amphiphilic ICG are initially self-assembled to generate carrier-free nanoparticles. The obtained BI NPs demonstrated NIR-responsive drug release behavior and better photothermal conversion efficiency of up to 36%. In addition, BI NPs stimulated by NIR laser exhibited remarkable antibacterial activity, which realized the synergistic antibacterial treatment and promoted infected wound healing. In summary, the current research results provided a candidate strategy for self-assembling new BI NPs to treat bacterial infections synergistically.

A mitochondria-targeting self-assembled carrier-free lonidamine nanodrug for redox-activated drug release to enhance cancer chemotherapy.

Mitochondria play a vital role in maintaining cellular homeostasis. In recent years, studies have found that mitochondria have an important role in the occurrence and development of tumors, and targeting mitochondria has become a new strategy for tumor treatment. Lonidamine (LND), as a hexokinase inhibitor, can block the energy supply and destroy mitochondria. However, poor water solubility and low mitochondrial selectivity limit its clinical application. To overcome these obstacles, we report redox-activated self-assembled carrier-free nanoparticles (Cy-TK-LND NPs) based on a small molecule prodrug, in which photosensitizer IR780 (Cy) which targets mitochondria is conjugated to LND via a sensitive thioketal (TK) linker. Intracellular oxidative stress induced by laser radiation leads to the responsive cleavage of Cy-TK-LND NPs, facilitating the release of free LND into mitochondria. Subsequently, LND damages mitochondria, triggering the apoptosis pathway. The results show the effective killing effect of Cy-TK-LND NPs on cancer cells in vitro and in vivo. The IC50 value of irradiated Cy-TK-LND NPs is 5-fold lower than that of free LND. Moreover, tumor tissue section staining results demonstrate that irradiated Cy-TK-LND NPs induce necrosis and apoptosis of tumor cells, upregulate cytochrome C and pro-apoptotic Bax, and downregulate anti-apoptotic Bcl-2. Generally, Cy-TK-LND NPs exhibit efficient mitochondria-targeted delivery to improve the medicinal availability of LND. Accordingly, such a carrier-free prodrug-based nanomedicine holds promise as an effective cancer chemotherapy strategy.