Jimin Zhang

Photodynamic therapy (PDT) holds great promise for cancer treatment owing to its spatiotemporal selectivity and minimal invasiveness. However, its therapeutic efficacy is hampered by photosensitizer self-quenching and intrinsic tumor hypoxia. Herein, we construct a tumor-microenvironment (TME)-activated dual-prodrug nanosystem (PheoA-CSSE-JSK) integrating the photosensitizer prodrug PheoA and nitric-oxide (NO) prodrug JSK for targeted tumor delivery. Tumor-abundant glutathione (GSH) cleaves disulfide bonds to restore the photoactivity of PheoA, which generates reactive oxygen species (ROS) under near-infrared irradiation. Meanwhile, intracellular GSH/glutathione S-transferase (GST) triggers NO release from JSK. NO-derived reactive nitrogen species (RNS) can degrade the tumor collagen matrix, which is inferred to potentially relieve hypoxia and further boost ROS production. GSH consumption, together with NO-mediated inhibition of the mitochondrial respiratory chain, may further augment ROS levels. We propose a self-reinforcing ROS-amplification working model involving PheoA photoactivation, potential NO-associated hypoxia alleviation, GSH depletion, and mitochondrial respiratory-chain inhibition. Collectively, these combined effects facilitate mitochondrial-dependent apoptosis and prominent antitumor outcomes. This TME-responsive dual-prodrug nanoplatform provides a promising strategy to augment PDT against hypoxic tumors.

Polymer-peptide conjugates are promising materials that can be widely applied in drug delivery, tissue engineering, and antibacterial coatings. Grafting peptides to a degradable polymer backbone as side chains enhances the loading capability of peptides, facilitates the regulation of self-assembly, and imparts degradability to the resulting assemblies. In this study, a series of degradable polyethylene glycol (PEG) derivative polymers, denoted as P(PEG), featuring disulfide linkages and adamantyl groups, are prepared through Passerini polymerization and then functionalized with β-cyclodextrin (β-CD)-modified peptide octa-arginine (R8) and mPEG through molecular recognition, affording peptide-grafted PEG-derivative polymers. The self-assembly behaviors of the peptide-grafted polymers are influenced by the molecular weight of PEG prepolymers and the number of conjugated R8 and mPEG. Assemblies including micelle-like nanoparticles, polymersomes ranging from 160 to 270 nm, and polymersomes over 1 μm with low polydispersity can be obtained by controlling the structure of the peptide-grafted polymer. The presence of the disulfide bonds within the P(PEG) backbone facilitates the degradation of the assemblies into fragments under 10 nm in 10 mM glutathione solution. The assembly with an appropriate size and zeta potential could be applied as a nanocarrier for the delivery of the model drug doxorubicin (DOX) into 4T1 cells, leading to the apoptosis of the cancer cells.

Hyperbranched polymers can be suitable polymeric scaffolds for the modification of functional groups and fabrication of applicable nanoparticles considering their good solubility, numerous modification sites, and unique self-assembly behaviors. To facilitate the modification process and obtain various functional hyperbranched polymers, a new inimer 2-((adamantan-1-yl)amino)-1-(4-((2-bromo-2-methylpropanoyl)oxy)phenyl)-2-oxoethyl methacrylate (ABMA) with an adamantyl group was prepared in this research through the Passerini reaction. ABMA was copolymerized with 2-(diisopropylamino)ethyl methacrylate (DPA), affording the pH-responsive hyperbranched polymer hPDPA. Model molecules poly(ethylene glycol) (PEG) and the peptide RRRRRRRRC (PArg) with a cell-penetrating octaarginine fragment were conjugated with β-cyclodextrin (β-CD) to modify the hPDPA through molecular recognition. The inclusion complex hPDPA/PEG self-assembled into micelles in phosphate buffer at pH 7.4, while hPDPA/PEG/PArg self-assembled into vesicles because of the repulsion of the positively charged PArg. It was demonstrated that the DOX-loaded hPDPA/PEG/PArg could be internalized by Hela cells with high efficiency and could induce apoptosis of Hela cells.

The primary challenges in the tissue engineering of small-diameter artificial blood vessels include inadequate mechanical properties and insufficient anticoagulation capabilities. To address these challenges, urea-pyrimidone (Upy)-based polyurethane elastomers (PIIU-B) were synthesized by incorporating quadruple hydrogen bonding within the polymer backbone. The synthesis process employed poly(L-lactide-ε-caprolactone) (PLCL) as the soft segment, while di-(isophorone diisocyanate)-Ureido pyrimidinone (IUI) and isophorone diisocyanate (IPDI) were utilized as the hard segment. The resulting PIIU-B small-diameter artificial blood vessel with a diameter of 4 mm was fabricated using the electrospinning technique, achieving an optimized IUI/IPDI composition ratio of 1:1. Enhanced by multiple hydrogen bonds, the vessels exhibited a robust elastic modulus of 12.45 MPa, an extracellular matrix (ECM)-mimetic nanofiber morphology, and a high porosity of 41.31%. Subsequently, the PIIU-B vessel underwent dual-functionalization with low-molecular-weight heparin and gelatin via ultraviolet (UV) crosslinking (designated as PIIU-B@LHep/Gel), which conferred superior biocompatibility and exceptional anticoagulation properties. The study revealed improved anti-platelet adhesion characteristics as well as a prolonged activated partial thromboplastin time (APTT) of 157.2 s and thrombin time (TT) of 64.2 s in vitro. Following a seven-day subcutaneous implantation, the PIIU-B@LHep/Gel vessel exhibited excellent biocompatibility, evidenced by complete integration with the surrounding peri-implant tissue, significant cell infiltration, and collagen formation in vivo. Consequently, polyurethane-based artificial blood vessels, reinforced by multiple hydrogen bonds and dual-functionalized with heparin and gelatin, present as promising candidates for vascular tissue engineering.

Insufficient drug accumulation in tumors severely limits the antitumor efficiency of hyaluronic acid (HA) nanomedicine in solid tumors due to superficial penetration depth, low cell uptake, and nonspecific drug release. Hence, we constructed a dual NO prodrug (alkynyl-JSK) and doxorubicin prodrug (cis-DOX)-conjugated HA nanoparticle (HA-DOX-JSK NPs), which achieved cascade-boosted drug delivery efficiency based on a relay strategy of NO-mediated deep tumor penetration─HA target CD44 tumor cell uptake─tumor microenvironment (TME)-responsive drug release. The nanoparticle demonstrated sustained and locoregionally GSH/GST-triggered NO release and GSH/pH-responsive DOX release in the tumor. The released NO first mediated collagen degradation, causing deep tumor penetration of nanoparticles in the dense extracellular matrix. Immediately, HA was relayed to enhance CD44-targeted tumor cell uptake, and then, the nanoparticles were finally triggered by specific TME to release DOX and NO in the deep tumor. Relying on the relayed delivery strategy, a significant improvement of DOX accumulation in tumors was realized. Moreover, NO depleted GSH-induced intracellular reactive oxygen species, enhancing DOX chemotherapy. Based on this strategy, the tumor inhibition rate in breast cancer was up to 87.8% in vivo. The relay drug-delivery HA system would greatly cascade-boost drug accumulation in deep tumors for efficient solid tumor therapy.

Bacterial infection‐induced excessive inflammation is a major obstacle in diabetic wound healing. Nitric oxide (NO) exhibits significant antibacterial activity but is extremely deficient in diabetes. Hence, a near‐infrared (NIR)‐triggered NO release system is constructed through codelivery of polyarginine (PArg) and gold nanorods (Au) in an NIR‐activatable methylene blue (MB) polypeptide‐assembled nanovesicle (Au/PEL‐PBA‐MB/PArg). Upon NIR irradiation, the quenched MB in the nanovesicles is photoactivated to generate more reactive oxygen species (ROS) to oxidize PArg and release NO in an on‐demand controlled manner. With the specific bacterial capture of phenylboronic acid (PBA), NO elevated membrane permeability and boosted bacterial vulnerability in the photothermal therapy (PTT) of the Au nanorods, which is displayed by superior mild PTT antibacterial activity against methicillin‐resistant Staphylococcus aureus (MRSA) at temperatures < 49.7 °C in vitro. Moreover, in vivo, the antibacterial nanovesicles greatly suppressed the burst of MRSA‐induced excessive inflammation, NO relayed immunomodulated macrophage polarization from M1 to M2, and the excessive inflammatory phase is successfully transferred to the repair phase. In cooperation with angiogenesis by NO, tissue regeneration is accelerated in MRSA‐infected diabetic wounds. Therefore, nanoplatform has considerable potential for accelerating the healing of infected diabetic wounds.

In this paper, a polyacrylic elastomer latex with butyl acrylate (BA) as the core and methyl methacrylate (MMA) copolymerized with glycidyl methacrylate (GMA) as the shell, named poly(BA-MMA-GMA) (PBMG), was synthesized by seeded emulsion polymerization. Cellulose nanocrystal (CNC) was dispersed in the polyacrylic latex to prepare PBMG/CNC dispersions with different CNC contents. The dried product was mixed with polylactic acid (PLA) to fabricate PLA/PBMG/CNC blends. The addition of PBMG and PBMG/CNC improved the mechanical properties of the PLA matrix. Differential scanning calorimetry (DSC) was used to investigate the non-isothermal crystallization kinetics. The Avrami equation modified by the Jeziorny, Ozawa and Mo equations was used to analyze the non-isothermal crystallization kinetics of PLA and its blends. Analysis of the crystallization halftime of non-isothermal conditions indicated that the overall rate of crystallization increased significantly at 1 wt% content of CNC. This seemed to result from the increase of nucleation density and the acceleration of segment movement in the presence of the CNC component. This phenomenon was verified by polarizing microscope observation.

In this paper, a polyacrylic elastomer latex with butyl acrylate (BA) as the core and methyl methacrylate (MMA) copolymerized with glycidyl methacrylate (GMA) as the shell, named poly(BA-MMA-GMA) (PBMG), was synthesized by seeded emulsion polymerization. Cellulose nanocrystal (CNC) was dispersed in the polyacrylic latex to prepare PBMG/CNC dispersions with different CNC contents. The dried product was mixed with polylactic acid (PLA) to fabricate PLA/PBMG/CNC blends. The addition of PBMG and PBMG/CNC improved the mechanical properties of the PLA matrix. Differential scanning calorimetry (DSC) was used to investigate the non-isothermal crystallization kinetics. The Avrami equation modified by Jeziorny, and the Ozawa, and Mo’s equations were used to analyze the nonisothermal crystallization kinetics of PLA and its blends. Analysis of crystallization halftime of nonisothermal conditions indicated that the overall rate of crystallization increased significantly at 1 wt% content of CNC. This seemed to result from the increase of nucleation density and the acceleration of segment movement in the presence of CNC component. This phenomenon was verified by polarizing microscope observation.