Polydopamine Nanostructure-Enhanced Water Interaction with pH-Responsive Manganese Sulfide Nanoclusters for Tumor Magnetic Resonance Contrast Enhancement and Synergistic Ferroptosis-Photothermal Therapy.

Rational structure design benefits the development of efficient nanoplatforms for tumor theranostic application. In this work, a multifunctional polydopamine (PDA)-coated manganese sulfide (MnS) nanocluster was prepared. The polyhydroxy structure of PDA enhanced the water interaction with pH-responsive MnS nanoclusters via hydrogen bonds. At pH 5.5 conditions, the spin-lattice relaxation rate of MnS nanoclusters dramatically increased from 5.76 to 19.33 mM-1·s-1 after the PDA coating, which can be beneficial for efficient tumor magnetic resonance imaging. In addition, PDA endowed MnS nanoclusters with excellent biocompatibility and good photothermal conversion efficiency, which can be used for efficient tumor photothermal therapy (PTT). Furthermore, MnS nanoclusters possess the ability to release H2S in the acidic tumor microenvironment, effectively inhibiting mitochondrial respiration and adenosine triphosphate production. As a result, the expression of heat shock protein was obviously reduced, which can reduce the resistance of tumor cells to photothermal stimulation and enhance the efficacy of PTT. The released Mn2+ also displayed efficient peroxidase and glutathione oxidase-like activity, effectively inducing tumor cell ferroptosis and apoptosis at the same time. Therefore, this nanoplatform could be a potential nanotheranostic for magnetic resonance contrast enhancement and synergistic ferroptosis-PTT of tumors.

CCR2-overexpressing biomimetic carrier-free nanoplatform for enhanced cascade ferroptosis tumor therapy.

Ferroptosis-based nanoplatforms have shown great potential in cancer therapy. However, they also face issues such as degradation and metabolism. Carrier-free nanoplatforms consisting of active drugs can effectively avoid the security issues associated with additional carrier ingredients. Herein, a biomimetic carrier-free nanoplatform (HESN@CM) was designed to treat cancer by modulating cascade metabolic pathways of ferroptosis. CCR2-overexpressing macrophage membrane-modified HESN can target cancer cells via the CCR2-CCL2 axis. The acidic tumor microenvironment (TME) can disrupt the supramolecular interaction of HESN, releasing hemin and erastin. Then, erastin could induce cancer cells ferroptosis by inhibiting system XC- pathways, while hemin, a vital component of blood to transport oxygen, could be broken down by heme oxygenase-1 (HO-1), increasing the intracellular Fe2+ concentration to induce cancer cells' ferroptosis further. Meanwhile, erastin could enhance the activity of HO-1, further promoting the release of Fe2+ from hemin. As a result, HESN@CM demonstrated superior therapeutic efficacy in both primary and metastatic tumors in vitro and in vivo. The carrier-free HESN@CM provided cascade ferroptosis tumor therapy strategies for potential clinical application. STATEMENT OF SIGNIFICANCE: CCR2-overexpressing biomimetic carrier-free nanoplatform (HESN@CM) was designed for cancer treatment by modulating metabolic pathways of ferroptosis. HESN modified with CCR2-overexpressing macrophage membrane can target tumor cells via the CCR2-CCL2 axis. HESN was composed of hemin and erastin without additional vectors. Erastin could directly induce ferroptosis, while hemin could be broken down by heme oxygenase-1 (HO-1), increasing the intracellular Fe2+ concentration to enhance ferroptosis further. Meanwhile, erastin could improve the activity of HO-1, promoting the release of Fe2+ from hemin. Therefore, HESN@CM with good bioavailability, stability, and simple preparation can realize cascade ferroptosis tumor therapy and have the potential prospect of clinical translation.

Self-assembled nanomaterials for ferroptosis-based cancer theranostics.

Most ferroptosis nanomedicines based on organic or inorganic carriers have difficulties in further clinical translation due to their serious side effects and complicated preparation. Self-assembled nanomedicines can reduce the biological toxicity caused by additional chemical modifications and excipients, offering better biocompatibility and safety. Ferroptosis therapy is an iron-associated programmed cell death dependent on lipid peroxidation with efficient tumor selectivity and biosafety. Therefore, the application of self-assembled nanomedicines with good biosafety in the ferroptosis treatment of tumors has attracted extensive attention. In this review, recent advances in the field of ferroptosis-based self-assembled nanomaterials for cancer therapy are presented, with emphasis on how these nanomaterial components interact and their distinct mechanisms for inducing ferroptosis in tumor cells, including iron metabolism, amino acid metabolism and CoQ/FSP1, as well as their respective advantages and challenges. This review would therefore help the spectrum of advanced and novice researchers interested in this area to quickly zoom in on the essential information and glean some thought-provoking ideas to advance this subfield in cancer nanomedicine.

Dye-cored polylysine dendrimer as luminescent nanoplatform for imaging-guided anticancer drug delivery.

Dendrimers have numerous applications in imaging and drug delivery. Designing a dendrimer diagnostic platform with a well-defined structure and controlled drug delivery is a formidable challenge. Here, we design dendritic polymer-platinum conjugates (G5-PEG-Pt) as pH-responsive nanovesicles for imaging-guided platinum drug delivery. The G5-PEG-Pt have a well-defined structure, intrinsically bright fluorescence, and acid-responsive drug release. The pH-responsive G5-PEG-Pt could rapidly release the platinum drug at acidic pH (5.0) than neutral pH (7.4). The G5-PEG-Pt could enter SKOV-3 human ovarian cancer cells by the endocytosis pathway and exhibited comparative cytotoxicity to free cisplatin. By virtue of the prolonged blood circulation time and the enhanced permeability and retention (EPR) effect, a 4.4-fold higher tumor platinum uptake than that of free cisplatin was achieved, potentially enhancing the therapeutic indexes of the platinum drug. Therefore, these pH-responsive platinum and fluorescent dendrimer conjugates are expected to be potent in vivo cancer optical imaging and therapy platforms.

A Polyoxometalate-Encapsulated Metal-Organic Framework Nanoplatform for Synergistic Photothermal-Chemotherapy and Anti-Inflammation of Ovarian Cancer.

Photothermal therapy (PTT), as a noninvasive and local treatment, has emerged as a promising anti-tumor strategy with minimal damage to normal tissue under spatiotemporally controllable irradiation. However, the necrosis of cancer cells during PTT will induce an inflammatory reaction, which may motivate tumor regeneration and resistance to therapy. In this study, polyoxometalates and a chloroquine diphosphate (CQ) co-loaded metal-organic framework nanoplatform with hyaluronic acid coating was constructed for efficient ovarian cancer therapy and anti-inflammation. Our results demonstrated that this nanoplatform not only displayed considerable photothermal therapeutic capacity under 808 nm near-infrared laser, but also had an impressive anti-inflammatory capacity by scavenging reactive oxygen species in the tumor microenvironment. CQ with pH dependence was used for the deacidification of lysosomes and the inhibition of autophagy, cutting off a self-protection pathway induced by cell necrosis-autophagy, and achieving the synergistic treatment of tumors. Therefore, we combined the excellent properties of these materials to synthesize a nanoplatform and explored its therapeutic effects in various aspects. This work provides a promising novel prospect for PTT/anti-inflammation/anti-autophagy combinations for efficient ovarian cancer treatment through the fine tuning of material design.

A Polydopamine-Coated Platinum Nanoplatform for Tumor-Targeted Photothermal Ablation and Migration Inhibition.

In this work, Arg-Gly-Asp (RGD) peptide-coupled polydopamine-modified mesoporous platinum nanoparticles (mPt@PDA-RGD NPs) were developed for targeted photothermal therapy (PTT) and migration inhibition of SKOV-3 cells. mPt@PDA-RGD NPs with obvious core/shell structure demonstrated high photothermal performance under 808-nm near-infrared (NIR) laser irradiation. mPt@PDA-RGD NPs with favorable biocompatibility exhibited remarkable SKOV-3 inhibition ability under NIR laser irradiation. Moreover, compared to mPt@PDA NPs, the RGD-functionalized NPs achieved more tumor uptake and PTT performance, which was attributed to the specific interaction between RGD of NPs and αvß3 integrin overexpressed by SKOV-3. Importantly, cell scratch experiments indicated that the photothermal effect of mPt@PDA-RGD NPs can effectively inhibit the migration of surviving SKOV-3 cells, which was assigned to disturbance of the actin cytoskeleton of SKOV-3. Thus, mPt@PDA-RGD NPs presented great potential for targeted tumor photothermal ablation and migration inhibition.

A near-infrared triggered upconversion/MoS2 nanoplatform for tumour-targeted chemo-photodynamic combination therapy.

The combination of photodynamic therapy and chemotherapy has shown a great potential in cancer treatment. As a promising photosensitizer, MoS2 quantum dots (QDs) have limited application due to the low tissue penetration of its light absorbing wavelength in the ultraviolet and visible regions. For the purpose of utilizing MoS2QDs in higher NIR absorption region, herein, we constructed a core/shell nano-photosensitizer upconversion@MoS2 with doxorubicin loading. This nanoplatform can convert 980 nm NIR into visible light, activating MoS2QDs to produce reactive oxygen species through fluorescence resonance energy transfer. In addition, this nanoplatform presented good biocompatibility and tumor targeting after polyethylene glycol and folic acid modification. Interestingly, with pH-responsive drug release performance, this nanoplatform presented efficient chemotherapy effects. Thus, the tumour-targeted nanoplatform can achieve up-converted luminescence imaging guided chemo-photodynamic synergistic therapy effectively.