ABSTRACT The development of polymer prodrugs with well-defined architectures capable of forming stable nanomicelles is important for achieving precise and efficient drug delivery. Compared with conventional linear systems, star-shaped copolymer prodrugs offer enhanced micellar stability owing to their covalently tethered architecture. However, many existing synthetic approaches rely on transition-metal catalyzed polymerization and customized monomers, which limit their sustainability and practical applicability. Herein, we report a pH-responsive doxorubicin (DOX)-conjugated benzaldehyde-functionalized star-shaped copolymer synthesized via an environmentally benign metal-free atom transfer radical polymerization (ATRP) strategy. A hydroxyl-functionalized star-shaped copolymer scaffold was first prepared from readily available monomers and subsequently modified to introduce pendant benzaldehyde groups, enabling DOX conjugation through acid-labile imine linkages. This approach affords well-controlled polymer architectures while avoiding transition-metal residues and the need for pre-functionalized monomers. The resulting DOX-conjugated star-shaped copolymers form unimolecular micelles with high colloidal stability and exhibit pH-triggered drug release under acidic conditions. In vitro studies further demonstrate effective cellular internalization and a moderated cytotoxic profile toward human large-cell lung carcinoma (H460) cells, supporting the functional viability of this micellar system as a polymer prodrug delivery platform.

Novel POSS unimolecular micelles for drug delivery

Liver fibrosis is a chronic liver disease driven by sustained inflammation, highlighting the need for targeted delivery of anti-inflammatory agents. We report the design of an acid-sensitive, liver-targeted hyperbranched polyprodrug (PPOG) that forms stable unimolecular micelles. Prednisone is conjugated to the hydrophobic core through acid-labile linkers, and glycyrrhetinic acid on the micelle surface enables hepatocyte targeting. PPOG demonstrates excellent colloidal stability under dilution, ionic stress, and long-term storage. In vitro, the micelles show low cytotoxicity and rapid prednisone release under acidic conditions. GA-mediated targeting enhances cellular uptake in hepatocytes, while in vivo imaging in a CCl4-induced mouse fibrosis model confirms higher liver accumulation than nontargeted micelles. PPOG treatment markedly reduces liver injury biomarkers, inflammatory cytokines, and collagen deposition, outperforming free prednisone and nontargeted formulations. These results indicate that PPOG unimolecular micelles offer a promising strategy for targeted anti-inflammatory therapy in liver fibrosis.

Abstract Fluorescence imaging in the second near‐infrared window (NIR‐II) enables deep‐tissue visualization with high spatial–temporal resolution. Developing molecular fluorophores with high brightness and stability in aqueous media is therefore critical. However, most NIR‐II excited fluorophores suffer from pronounced nonradiative decay and fluorescence quenching in water. Here, we propose a unimolecular micellization strategy to construct high‐brightness NIR‐II fluorophores that self‐assemble into stable unimolecular micelles (UIMs) in aqueous solution. The designed star‐shaped amphiphilic molecule IR‐FCT8CP carries long alkyl chains that collapse into a compact hydrophobic core upon micellization, effectively shielding the fluorophore from water‐induced quenching and restricting intermolecular interactions. The resulting IR‐FCT8CP UIMs exhibit absorption and emission maxima at 979 and 1181 nm, respectively, with a quantum yield of 0.05% and a molar absorption coefficient of 1.67 × 10 4 M −1 ·cm −1 in aqueous solution, yielding higher brightness than IR‐FCDP and IR‐FCTP UIMs. The IR‐FCT8CP UIMs enable dynamic in vivo vascular imaging under 1064 nm excitation using a 1500 nm long‐pass filter, clearly resolving vascular networks with a high signal‐to‐background ratio. This unimolecular micellization strategy offers a general design concept for developing stable, high‐brightness NIR‐II molecular fluorophores for efficient bioimaging in physiological environments.

Fluorescence imaging in the second near-infrared window (NIR-II) enables deep-tissue visualization with high spatial-temporal resolution. Developing molecular fluorophores with high brightness and stability in aqueous media is therefore critical. However, most NIR-II excited fluorophores suffer from pronounced nonradiative decay and fluorescence quenching in water. Here, we propose a unimolecular micellization strategy to construct high-brightness NIR-II fluorophores that self-assemble into stable unimolecular micelles (UIMs) in aqueous solution. The designed star-shaped amphiphilic molecule IR-FCT8CP carries long alkyl chains that collapse into a compact hydrophobic core upon micellization, effectively shielding the fluorophore from water-induced quenching and restricting intermolecular interactions. The resulting IR-FCT8CP UIMs exhibit absorption and emission maxima at 979 and 1181nm, respectively, with a quantum yield of 0.05% and a molar absorption coefficient of 1.67×104 M-1·cm-1 in aqueous solution, yielding higher brightness than IR-FCDP and IR-FCTP UIMs. The IR-FCT8CP UIMs enable dynamic in vivo vascular imaging under 1064nm excitation using a 1500nm long-pass filter, clearly resolving vascular networks with a high signal-to-background ratio. This unimolecular micellization strategy offers a general design concept for developing stable, high-brightness NIR-II molecular fluorophores for efficient bioimaging in physiological environments.

Chiral nanocomposites have attracted much attention due to their fascinating size-dependent characteristics. Such nanomaterials could be precisely synthesized by templates from randomly coiled unimolecular micelles with poor chiroptical activities. Helical polymers possessing secondary chirality usually display stronger chiral induction than random-coiled polymers do. However, the controllable preparation of helical unimolecular micelles still remains challenging, which hinders the investigation into the effect of morphology and size on chiroptical properties. In this study, multiarmed star-shaped poly-(phenylacetylene)-s (PPAs) with target composition, molecular weight, and size were precisely prepared from the multisited initiator via living polymerization. Based on acid-base interactions, chiral transfer from PPAs to various dyes was accomplished in composite membranes and suspension. Notably, the chiral nanocomposites consisting of star-shaped PPAs displayed enhanced helical stability, Cotton effect, and circularly polarized luminescence (CPL) compared with linear analogues. Furthermore, this system displayed the triple-mode (photoluminescence, circular dichroism, and CPL) detection toward the volatile organic compound for environmental monitoring.

Dendritic polymer-based unimolecular micelles have attracted more interest in tumor chemotherapy. However, the drug release behavior was significantly affected by the hydrophilic-hydrophobic property of the dendritic cores. In the present work, carbon quantum dot (CQD) was used as a bridge between the dendritic core and drug to achieve a better drug release performance for imaging-mediated therapy. Strawberry-shaped hybrid prodrug was designed with aDOX content of 16.7%. The resultant hybrid unimolecular micelles with a mean hydrodynamic diameter of around 82nm showed sustained acid-triggered DOX release with minimized drug leakage, possessing enhanced anti-tumor efficacy compared to free DOX. Furthermore, the fluorescence of the hybrid unimolecular micelles could be turned on for imaging-guided cancer therapy after tumor intracellular drug release.

π-Conjugated fluorophores show great potential for NIR-II bio-imaging owing to their superior brightness and photostability, yet their clinical translation has been hindered by suboptimal pharmacokinetics. To address this issue, a strategy is developed to tailor the in vivo behavior of π-conjugate fluorophores by breaking π-π stacking in polymer brush-engineered unimolecular micelles. This approach marks a significant shift from traditional methods of tuning micelles, which rely on varying the hydrophilic-to-hydrophobic ratios and are often ineffective for π-conjugated systems due to the dominance of π-π interactions. By disrupting π-π interactions in the unimolecular micelles, pharmacokinetics and photophysical properties can be precisely controlled by systematically varying the molecular weight and composition of the polymer brushes. Accordingly, the blood circulation half-life can be adjusted across a 60-fold range, and fluorescence emissions are improved by 47-fold, facilitating adaptive fluorophore applications from kidney dysfunction detection to tumor imaging. Additionally, the engineered unimolecular micelles exhibit reduced nonspecific uptake and improved tumor targeting efficiency, resulting in a 5-fold higher tumor-to-liver ratio than conventional π-π stacked nano-aggregates. These findings offer a solid solution to the pharmacokinetic optimization issues and provide a new design principle for π-conjugated phototheranostic materials.

Supramolecular assemblies hold great promise for advanced chiral materials because of their structural diversity and dynamic features, but their low chiroptical activity limits practical applications. We report hierarchical supramolecular assemblies with giant chiroptical activity and mechanical attributes achieved through coassembly of achiral amphiphilic unimolecular micelles and chiral additives. Chiral fibrillar assemblies emerge from the nanostructured environment imposed by the micelles, driven by progressive chirality transfer through multiple hydrogen bonds between components. Integrating multifarious achiral luminescent molecules and nanocrystals into these assemblies leads to full-color circularly polarized luminescence-active materials with dissymmetry factors of ~10-1. A concentration-dependent chirality inversion is accessed through tailoring the coassembly kinetics. This strategy enables efficient red CPL, crucial for quantum and optical technologies.

Targeting Aurora Kinase A (AURKA) to modulate RalA activation offers a promising strategy for tumor suppression in Ras-independent and Ras-dependent cancers. However, clinical use of the AURKA inhibitor MLN8237 (Alisertib) is limited by its hydrophobicity and poor water solubility. To overcome these limitations, here, we developed an enzyme-biodegradable unimolecular micelle (UMM) nanoparticle to deliver MLN8237 (NPMLN) and evaluated its therapeutic efficacy in tumor xenograft models. NPMLN selectively inhibited AURKA, downregulated pSer194 RalA, and suppressed anchorage-independent growth in SKOV3 (Ras-independent) and MIA PaCa-2 (Ras-dependent) cancer cells. Nanoparticles loaded with sulforhodamine B (NPSRB) and IR780 (NPIR780) confirmed enhanced cellular uptake and tumor localization, respectively. Improved solubility and bioavailability enabled low-dose parenteral delivery of MLN8237, achieving significant tumor regression compared to free drug. This correlated with inhibition of AURKA and RalA phosphorylation (pSer194RalA) in both tumors. Together, they highlight the therapeutic potential of NPMLN in targeting AURKA-RalA crosstalk in tumor xenografts.

Uncontrolled rapture of prodrug nano-formulation under physiological concentration gradient is a bottleneck in the effective delivery of anticancer drugs to solid tumors in vivo. The present investigation reports macromolecular nano-compartmentalization in single polymer chain micellar nanoparticle (or unimolecular micelle nanoparticle, UMNp) and demonstrates its therapeutic efficacies in pancreatic cancer xenograft mouse model. The UMNp is engineered in a six-arm enzymatic-biodegradable polycaprolactone star-polymer by employing a divergent approach using identical chemical constituents but varying the arms-lengths. The tiny <25nm sized core-shell UMNp is found to be non-toxic, non-hemolytic, and highly efficient in loading 14% of clinical drug doxorubicin (DOX). UMNp undergoes biodegradation at the intracellular endo-lysosomal compartments and exhibited substantial growth inhibition in multiple cancer cell lines such as MCF-7 (breast cancer), MDA-MB-231 and MDA-MB-468 (triple-negative breast cancers), and MIA PaCa 2 (pancreatic cancer) at very low IC50 values. Strikingly, the DOX delivered from the UMNp platform demonstrate more than a 90% reduction in tumor volume in MIA PaCa 2 tumor-bearing mice. Biodistribution via IVIS-imaging using deep tissue-penetrable near-infrared IR-780-loaded UMNp establish high tissue penetration and longer retention in tumor-bearing mice and substantiate their excellent efficacy in solid tumor regression.

Carbon dots (CDs) are promising fluorescent nanomaterials, however, they are often hindered by aggregation caused quenching (ACQ) in solid‐state application because of close π–π stacking interactions. Furthermore, the challenges still exist in the development of CDs‐based solid‐state fluorescent materials with stable structure and high fluorescence intensity. To address this challenge, a general and robust polymer directed nanoconfined self‐assembly strategy is developed, enabling the fabrication of regular morphology, structurally ultra‐stable and solid‐state fluorescent CDs assemblies using hydrophilic star‐liked di‐block copolymer unimolecular micelles as templates. The absolute photoluminescence quantum yield (PLQY) of these fluorescent solid‐state CD assemblies reaches 21.46%, significantly higher than 0.12% observed in traditional ACQ solid‐state CDs. The enhanced solid‐state fluorescent property is attributed to the prevention of the π–π stacking of CDs, the restricted movement of surface groups and the suppression of non‐radiative transition processes via the polymer directed nanoconfined self‐assembly of CDs. The fluorescence intensity of CDs assemblies can also be precisely tuned by adjusting the polymerization time of polymer template. Based on these advantages, the CDs assemblies are employed as luminescent materials in the identification of latent fingerprints (LFP), flexible films and 3D printing functional hydrogels.

ABSTRACTInternal emulsification emulsions are environmentally friendly and do not emit volatile organic compounds (VOCs). However, their micelle interface, dominated by ionic hydrophilic groups, hinders cross‐linking reactions and affects performance. We proposed a dual‐functional micellar interface (DFMI) that distributes both ionic and reactive hydrophilic groups, enhancing cross‐linking performance without significantly compromising emulsification properties. In this study, a series of sugar‐based hyperbranched waterborne polyurethane emulsions were synthesized with 2,2‐dimethylolpropionic acid (DMPA) as the ionic hydrophilic moiety. Dopamine (DA) was introduced at varying levels as the reactive hydrophilic moiety for terminal modification. The results showed that monomolecular micelles and vesicular micelles could be formed by symmetric and asymmetric modification of terminal DA. Symmetric modification tended to form unimolecular micelles, while asymmetric modification tended to form vesicular structures. Adhesion tests conducted after cross‐linking with gelatin showed that the asymmetrically modified adhesives with seven‐layer structured DA exhibited better cross‐linking degrees. Adhesion performance and swelling tests confirmed that the asymmetric structure exposed more terminal reactive groups, enhancing the utilization of the modified groups, as indicated by dynamic light scattering (DLS) for emulsion particle size and surface zeta potential. This study successfully prepared hyperbranched polyurethane emulsions with tunable micelle morphology, balancing emulsification ability, and cross‐linking degree, supporting the controlled emulsification of hyperbranched polymers and the development of bio‐based adhesives.

Dually fluorinated unimolecular micelles for stable oxygen-carrying and enhanced photosensitive efficiency to boost photodynamic therapy against hypoxic tumors.

Pearl-Necklace to Unimolecular Micelle Formation by Heterograft Bottlebrush Polymers in Solution

Unimolecular micelles (UMs) are nano-sized structures that are composed of single molecules with precise composition. Compared to self-assembled polymeric micelles, UMs possess ultra-stable property even in complex biological environment. With the development of controllable polymerization and coupling chemistry, the preparation of narrowly monodispersed UMs with precise morphology and size has been realized, which further facilitates their multifunctional applications. After brief introduction, state-of-the-art advances in the synthesis and applications of UMs are discussed with an emphasis on their bioapplications. It is believed that these UMs have great potential in future fabrication of multifunctional nanoplatforms.

Novel non-fluorinated surfactants for emulsion polymerization of fluorinated monomers

Preparation of Porphyrin-Based Unimolecular Micelles for Synergistic Photodynamic Therapy and Radiotherapy

Chiral plasmonic nanostructures exhibit potential in the advanced manufacturing industry, due to their fascinating characteristics. However, the limitation of existing fabrication methods as difficulty to precisely manipulate chiral nanostructures at the nanoscale restricts their application and optimization of performance. In this work, we report a simple and robust route for the precise construction of chiral Au nanoparticles (NPs), employing star-like block copolymers with well-defined structures as chiral templates. The globular unimolecular micelles as nanoreactors enabled control over the size, shape, and chirality of in situ grown nanocrystals. Utilizing the chiral anisotropy property of surface-enhanced Raman scattering (SERS), the enantioselective discrimination on various substrates was accomplished with an enhancement factor over 9.3 × 106. NPs with a smaller size exhibited strengthened Raman enhancement and chiral recognition. Furthermore, these chiral unimolecular-micelle-based templates with high efficiency and strong controllability could pave the way for tailor-made chiral nanomaterials.

It is crucial to use simple methods to prepare stable polymeric micelles with multiple functions for cancer treatment. Herein, via a "bottom-up" strategy, we reported the fabrication of β-CD-(PEOSMA-PCPTMA-PPEGMA)21 (βPECP) unimolecular micelles that could simultaneously treat tumors and bacteria with chemotherapy and photodynamic therapy (PDT). The unimolecular micelles consisted of a 21-arm β-cyclodextrin (β-CD) core as a macromolecular initiator, photosensitizer eosin Y (EOS-Y) monomer EOSMA, anticancer drug camptothecin (CPT) monomer, and a hydrophilic shell PEGMA. Camptothecin monomer (CPTMA) could achieve controlled release of the CPT due to the presence of responsively broken disulfide bonds. PEGMA enhanced the biocompatibility of micelles as a hydrophilic shell. Two βPECP with different lengths were synthesized by modulating reaction conditions and the proportion of monomers, which both were self-assembled to unimolecular micelles in water. βPECP unimolecular micelles with higher EOS-Y/CPT content exhibited more excellent 1O2 production, in vitro drug release efficiency, higher cytotoxicity, and superior antibacterial activity. Also, we carried out simulations of the self-assembly and CPT release process of micelles, which agreed with the experiments. This nanosystem, which combines antimicrobial and antitumor functions, provides new ideas for bacteria-mediated tumor clinical chemoresistance.