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Gas therapy, an emerging cancer treatment method of inflammation‐related diseases, has recently received substantial attention. The rapid advances in nanomedicine and nanotechnology have made gas precision treatment possible through tumor targeted delivery and controlled release of therapeutic agents. Single therapeutic is often inevitably accompanied with limited therapy efficacy. Gas therapy combined with other treatment methods can sensitize different therapy modes to augment cancer therapy. Understanding the mechanism through which gas enhances other therapeutic modalities will enable the design of reasonable strategies for clinical cancer therapy. In this review, we summarize novel gas‐based nanomedicines, focusing on gas‐based nanomedicine carriers, along with the release of gas molecules and the mechanisms of gas enhanced therapy. We describe the design of novel gas‐releasing nanoplatforms and the underlying synergistic mechanisms against cancer. Moreover, we describe the current challenges and outlook for future prospects in novel gas‐based nanomedicines for gas therapy in cancer. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC), a management of aggressive breast cancer, remains an unmet medical challenge. Although a wave of efforts had spurred to design novel therapeutic method of TNBC, unpredictable prognosis with lacking effective therapeutic targets along with the resistance to apoptosis seriously limited survival benefits. Ferroptosis is a non-apoptotic form of cell death that is induced by excessive lipid peroxidation, which provide an innovative way to combat cancer. Emerging evidence suggests that ferroptosis plays an important role in the treatment of TNBC cells. Herein, a novel ferroptosis nanomedicine was prepared by loading simvastatin (SIM), a ferroptosis drug, into zwitterionic polymer coated magnetic nanoparticles (Fe3O4@PCBMA) to improve the therapeutic effect of TNBC. The as-obtained Fe3O4@PCBMA-SIM nanoparticles demonstrated more cytotoxicity against MDA-MB-231 than MCF-7 due to the higher expression of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR), which demonstrated that statins could effectively kill TNBC. Further experiments showed that SIM could inhibit the expression of HMGCR to downregulate the mevalonate (MVA) pathway and glutathione peroxidase 4 (GPX4), thereby inducing cancer cell ferroptosis. What's more, PCBMA endows Fe3O4@PCBMA longer blood circulation performance to enhance their accumulation at tumor sites. Given that Fe3O4 have proven for clinical applications by the U.S. Food and Drug Administration (FDA) and SIM could induce cancer cell ferroptosis, the developed Fe3O4@PCBMA-SIM nanosystem would have great potential in clinics for overcoming the drug resistance brought about by apoptotic drugs to cancer cells. [ABSTRACT FROM AUTHOR]

Abstract: Noninvasive near‐infrared (NIR) light responsive therapy is a promising cancer treatment modality; however, some inherent drawbacks of conventional phototherapy heavily restrict its application in clinic. Rather than producing heat or reactive oxygen species in conventional NIR treatment, here a multifunctional yolk–shell nanoplatform is proposed that is able to generate microbubbles to destruct cancer cells upon NIR laser irradiation. Besides, the therapeutic effect is highly improved through the coalition of small interfering RNA (siRNA), which is codelivered by the nanoplatform. In vitro experiments demonstrate that siRNA significantly inhibits expression of protective proteins and reduces the tolerance of cancer cells to bubble‐induced environmental damage. In this way, higher cytotoxicity is achieved by utilizing the yolk–shell nanoparticles than treated with the same nanoparticles missing siRNA under NIR laser irradiation. After surface modification with polyethylene glycol and transferrin, the yolk–shell nanoparticles can target tumors selectively, as demonstrated from the photoacoustic and ultrasonic imaging in vivo. The yolk–shell nanoplatform shows outstanding tumor regression with minimal side effects under NIR laser irradiation. Therefore, the multifunctional nanoparticles that combining bubble‐induced mechanical effect with RNA interference are expected to be an effective NIR light responsive oncotherapy. [ABSTRACT FROM AUTHOR]

The potential therapeutic implications of nitric oxide (NO) for diverse diseases have been under consideration for years; however, the development of precisely controllable NO generation system with potential for clinical application has remained elusive. Herein, intelligent near-infrared (NIR) laser-triggered NO nanogenerators for the treatment of multidrug-resistant (MDR) cancer are fabricated by integrating photothermal agents and heat-sensitive NO donors into a single nanoparticle. Such nanogenerators can absorb 808 nm NIR photons and convert them into ample heat to trigger NO release. The generated NO molecules are demonstrated to successfully achieve multidrug-resistance reversal by inhibiting the expression of P-glycol protein. Consequently, the intracellular accumulation of doxorubicin is effectively increased, resulting in high toxicity to MDR cancer cells in vitro. By virtue of surface modification with targeting ligands, these nanoparticles are able to selectively accumulate in tumor tissue. The therapeutic effects of the nanogenerators are validated in a humanized MDR cancer model. The in vivo experiment indicates that the nanoparticles possess excellent tumor suppression functionality with few side effects upon NIR laser exposure. Therefore, this novel photothermal conversion-based NO-releasing platform is expected to be a potential alternative to clinical MDR cancer treatment and may provide insights with regard to other NO-relevant medical treatments. [ABSTRACT FROM AUTHOR]

[Display omitted] • Ferroptosis could effectively kill cancer cells because of their high-loaded reactive oxygen species (ROS), metabolic mutations, and increased requirement for an iron supply. • Ferric metal–organic frameworks (Fe-MOFs) function as nanoplatforms to co-deliver iron ions and a ferroptosis inducer, atorvastatin (ATV), to cancer cells. • The glutathione (GSH)-degradable zwitterionic polymer membrane (PMPC) coated on the surface endowed Fe-MOFs with enhanced stability and long circulation time. • When internalized by cancer cells, these nanoparticles were degraded by GSH, to deplete GSH and release ATV and Fe2+. • The ferroptosis mechanism of this nanoplatform was elucidated. Ferroptosis inhibits tumor growth by iron-dependently accumulating lipid peroxides (LPO) to a lethal extent, which can result from iron overload and glutathione peroxidase 4 (GPX4) inactivation. In this study, we developed biodegradable zwitterionic polymer-cloaked atorvastatin (ATV)-loaded ferric metal–organic frameworks (Fe-MOFs) for cancer treatment. Fe-MOFs served as nanoplatforms to co-deliver ferrous ions and ATV to cancer cells; the zwitterionic polymer membrane extended the circulation time of the nanoparticles and increased their accumulation at tumor sites. In cancer cells, the structure of the Fe-MOFs collapsed in the presence of glutathione (GSH), leading to the depletion of GSH and the release of ATV and Fe2+. The released ATV decreased mevalonate biosynthesis and GSH, resulting in GPX4 attenuation. A large number of reactive oxygen species were generated by the Fe2+-triggered Fenton reaction. This synergistic effect ultimately contributed to a lethal accumulation of LPO, causing cancer cell death. The findings both in vitro and in vivo suggested that this ferroptosis-inducing nanoplatform exhibited enhanced anticancer efficacy and preferable biocompatibility, which could provide a feasible strategy for anticancer therapy. [ABSTRACT FROM AUTHOR]

Photothermal therapy (PTT) has represented a promising noninvasive approach for cancer treatment in recent years. However, there still remain challenges in developing non-toxic and biodegradable biomaterials with high photothermal efficiency in vivo . Herein, we explored natural melanin nanoparticles extracted from living cuttlefish as effective photothermal agents and developed red blood cell (RBC) membrane-camouflaged melanin (Melanin@RBC) nanoparticles as a platform for in vivo antitumor PTT. The as-obtained natural melanin nanoparticles demonstrated strong absorption at NIR region, higher photothermal conversion efficiency (∼40%) than synthesized melanin-like polydopamine nanoparticles (∼29%), as well as favorable biocompatibility and biodegradability. It was shown that RBC membrane coating on melanin nanoparticles retained their excellent photothermal property, enhanced their blood retention and effectively improved their accumulation at tumor sites. With the guidance of their inherited photoacoustic imaging capability, optimal accumulation of Melanin@RBC at tumors was achieved around 4 h post intravenous injection. Upon irradiation by an 808-nm laser, the developed Melanin@RBC nanoparticles exhibited significantly higher PTT efficacy than that of bare melanin nanoparticles in A549 tumor-bearing mice. Given that both melanin nanoparticles and RBC membrane are native biomaterials, the developed Melanin@RBC platform could have great potential in clinics for anticancer PTT. [ABSTRACT FROM AUTHOR]

The development of cancer photothermal therapies, many of which rely on photothermal agents, has received significant attention in recent years. In this work, various ligands-stabilized magnetite (Fe3O4) particles are fabricated and utilized as a photothermal agents for in vivo tumor-imaging-guided photothermal therapy. Fe3O4 particles stabilized by macromolecular ligands as, e.g. polyethylene glycol (PEG), exhibit a superior and more stable photothermal effect compared to Fe3O4 particles stabilized by small molecules like citrate, due to their stronger ability of antioxidation. In addition, the photothermal effect of Fe3O4 particles is revealed to increase with size, which is attributed to the redshift of Vis-NIR spectra. Fe3O4 particles injected intravenously into mice can be accumulated in the tumor by the application of an external magnetic field, as revealed by magnetic resonance imaging. In vivo photothermal therapy test of PEG-stabilized Fe3O4 further achieves better tumor ablation effect. Overall, this study demonstrates efficient imaging-guided photothermal therapy of cancer that is based on Fe3O4 particles of optimized size and with optimized ligands. It is expected that the ligand-directed and size-dependent photothermal effect will provide more approaches in the design of novel materials. [ABSTRACT FROM AUTHOR]

Abstract: pH-sensitive poly(l-glutamic acid) grafted mesoporous silica nanoparticles (MSN-PLGA) were prepared by the surface-initiated N-carboxyanhydride polymerization method. The resultant MSN-PLGA was well dispersed in aqueous medium and showed high drug loading efficiency, superior stability, and significantly higher drug release rates. The cumulative release of doxorubicin hydrochloride (DOX) from DOX-loaded MSN-PLGA (DOX@MSN-PLGA) was pH-dependent and the release rate was much higher at pH 5.5 than that at pH 7.4. The cytotoxicity results indicated that the blank MSN-PLGA was biocompatible and the DOX@MSN-PLGA had potent in vitro cytotoxicity effect similar to free DOX. Overall, these results demonstrate that MSN-PLGA is a promising platform to build pH controlled drug delivery systems for cancer therapy. [Copyright &y& Elsevier]

The design of bioresponsive controlled drug delivery systems isa promising approach in cancer therapy, but it still is a major challengecapable of optimum therapeutic efficacy, i.e. no premature drug leakagein blood circulation while having a rapid and complete release intumor tissues. In this work, a kind of PEGylated core/shell structuredcomposite nanoparticle was developed via precipitation polymerization,where a disulfide-cross-linked poly(N-vinylcaprolactam-co-methacrylic acid) (P(VCL-s-s-MAA)) polymer shell was created to act as sheddable thermo/pH-sensitivegatekeepers, and a carboxylic acid modified mesoporous silica nanoparticles(MSN-COOH) core was applicable as an accessible reservoir to encapsulatehigh drug doses. At physiological conditions, the P(VCL-s-s-MAA)-PEG shell underwent a distinct transitionfrom a swollen state in pH 7.4 to a collapsed state in pH 5.0. Thoughsufficiently stable in water, composite nanoparticles were prone tofast dissociation and rupture when subjecting to 10 mM glutathione(GSH), due to the shedding of polymer walls through reductive cleavageof intermediate disulfide bonds, so that the polymer shell was activein moderating the diffusion of embedded drugs in-and-out of MSN channels.The cumulative in vitrorelease of DOX-loaded compositenanoparticles allowed a low trace of DOX diffusion below volume phasetransition temperature (VPTT) and a significant release rate aboveits VPTT, while the most rapid and perfect release was achieved undera reductive environment (pH 6.5 and 10 mM GSH), mimicking that ofintracellular cytosol compartments. The in vitrocellassay of blank carriers to normal cells indicated that the compositenanoparticles were suitable as drug carriers, but DOX-loaded carriershad a similar intensive toxicity to cancer cells compared with freeDOX. Therefore, these stimuli-responsive composite nanoparticles witha reductively sheddable and thermo/pH-responsive polymer shell gatecould, in principle, be applied for in vivocancertherapy, and synergistic drug delivery can be accomplished “justin time” in a precise event over the location. [ABSTRACT FROM AUTHOR]

Abstract: pH-responsive polymer shell chitosan/poly (methacrylic acid) (CS-PMAA) was coated on mesoporous silica nanoparticles (MSN) through the facile in situ polymerization method. The resultant composite microspheres showed a flexible control over shell thickness, surface charges and hydrodynamic size by adjusting the feeding amount of MSN and the molar ratio of [–NH2]/MAA. The MSN/CS-PMAA composite microspheres were stable in the pH range of 5–8 as well as in the physiological saline (0.15M NaCl). Doxorubicin hydrochloride (DOX) was applied as a model drug to investigate the drug storage and release behavior. The results demonstrated that DOX could be effectively loaded into the composite microspheres. The cumulative release of DOX-loaded composite microspheres was pH dependent and the release rate was much faster at low pH (5.5) than that of pH 7.4. The cytotoxicity test by MTT assay showed that the blank carrier MSN/CS-PMAA microspheres were suitable as drug carriers. The cellular uptake of composite microspheres was investigated by confocal laser scanning microscopy (CLSM), which indicated that MSN/CS-PMAA could deliver the drugs into HeLa cell. The above results imply that the composite microspheres are a promising drug delivery system for cancer therapy. [Copyright &y& Elsevier]