Exploring the natural availability and intrinsic bioactivity of blood-derived proteins opens new avenues for fabricating bioactive and patient-specific solutions for biomedical applications. Despite their several advantages, their use as inks for 3D printing is limited due to suboptimal rheological properties. To address this, we propose a dual-step strategy based on the initial generation of blood protein-based bulk hydrogels encompassing pristine and photo-responsive protein mixtures to allow their mechanical granularization followed by jamming, establishing injectable and printable granular inks. In this study, two globular-based protein matrices—human platelet lysates (PL) and bovine serum albumin (BSA)—were used as granular inks for 3D printing. We hypothesize that nozzle jamming—in contrast to the typically employed centrifugal jamming—would render optimized results for the granular protein inks’ processability. Printability was evaluated in filaments, scaffold grids, and convoluted structures. Taking advantage of the previously introduced photocurable moieties, post-printing photocrosslinking was used for the annealing of the microgels, leading to increased scaffold mechanical stability and robustness. The nozzle jamming methodology imparted the best print performance and reproducibility, where PLMA-based inks outperformed the BSAMA-based. In addition, the microgel granular constructs allowed primary human-derived adipose stem cells to adhere and proliferate, whereas the PLMA-based ink demonstrated higher cell affinity and enhanced biological performance. We further demonstrated that bioinks could be developed from PLMA-based inks, showcasing high viability without compromising 3D printing performance. Overall, this study gives clear insights into the importance of the jamming process as well as the granularization outcome requirements for the obtention of highly reproducible granular inks for 3D printing.

Multicolor circularly polarized luminescence (CPL) materials show considerable potential in the field of advanced anti-counterfeiting. However, it remains challenging to achieve stable inorganic materials with multicolor CPL. In this work, for the first time, chiroptical rare earth (RE) fluoride nanoparticles induced by helical silica are obtained through a facile in situ assembly strategy. The influence of assembly ratio and morphological structure on the luminescence dissymmetry factor (g_lum) has been systematically investigated, leading to an optimized g_lum value of 4.7 × 10⁻³. By adjusting the types and concentrations of RE dopants (Ce³⁺, Tb³⁺, Eu³⁺), the nanocomposites exhibit multicolor CPL and time-resolved photoluminescence characteristics. Remarkably, these nanocomposites retain their CPL activity even after calcination at 400°C. Leveraging the visible multicolor emissions, along with the hidden dynamic and chiroptical signals, the nanocomposites are successfully applied in high-security anti-counterfeiting patterns and multilevel optical encryption codes.

The field of molecular charge transfer cocrystals (CTCs) has advanced rapidly in recent years, with much work focused on their use in optoelectronic devices, photoacoustic imaging, photothermal therapy (PTT), optical waveguides, seawater desalination, and more. Organic photothermal CTCs are of particular interest because of their unique phototherapeutic effects in phototherapy and their remarkable imaging capabilities in fluorescence, magnetic resonance, and photoacoustic imaging, further enhancing their significance in medical applications. However, the use of photothermal CTCs in biomedicine has been limited, with few reported biological applications. Hence, there is a growing interest in CT-derived functional photothermal cocrystals potential contenders for targeted and controlled biomedical applications such as bacteria inhibition, cancer eradication, and tissue regeneration. This review offers insight into the recent advancements in crafting and producing CT-based materials with biomedical attributes. In addition, it outlines the current obstacles and future prospects in this burgeoning research domain, aiming to propel the continued advancement of CT-based biomaterials toward enhanced biomedical utilities. Overall, cocrystal-based near-infrared (NIR) photothermal materials have the potential to revolutionize a wide range of medical and technological applications and are an active area of research in chemistry, materials science, and nanotechnology.

Cell membrane coating (CMC) of nanoparticles (NPs) has emerged as a prominent strategy that has gained significant attention and achieved notable progress across various therapeutic sectors. Coating NPs with natural cell membranes endows them with various functions and addresses various challenges in drug delivery, such as prolonging circulation time, reducing immunogenicity, and improving targeting efficiency and cellular communication. Among the different NPs, lipid nanoparticles (LNPs) have revolutionized the field of nanomedicine by providing various advantageous features for drug delivery. The versatile characteristics of LNPs synergize well with cell membranes’ biomimetic properties, creating hybrid structures with enhanced functionalities for diverse biomedical applications. A more advanced form of LNPs with significantly enhanced capabilities can be achieved through CMC. However, significant opportunities remain for further advancements, with ongoing efforts focused on discovering innovative applications and fully harnessing the potential of this promising combination. This article provides a critical review of recent progress in cell membrane coated-LNPs (CMC-LNPs). First, different LNP types, their preparation methods, and coating strategies are summarized. The development, properties, functions, and applications of CMC-LNPs are then discussed. Last, their advantages, limitations, challenges, and future perspectives are presented.

Three-photon (3P) fluorescence imaging (FLI) utilizing excitation wavelengths within the near-infrared-III (NIR-III, 1600–1870 nm) window has emerged as a transformative modality for intravital imaging, owing to its combined advantages of excellent spatiotemporal resolution and remarkable tissue penetration. High-performance fluorescent probes are the cornerstone of high-quality NIR-III 3P FLI. However, the construction of such probes is often hindered by inherent trade-offs in molecular design principles, posing significant challenges for their performance optimization and practical application. Here, we propose a straightforward and effective strategy based on π-bridge manipulation to reconcile those competing molecular design parameters and substantially enhance 3P fluorescence properties. Leveraging this approach, a robust AIE-active small molecule, named TSSID, was developed, which exhibits bright NIR-I (700–950 nm) emission under 1665 nm NIR-III 3P excitation when formulated into nanoparticles (NPs). Remarkably, upon retro-orbital injection into mice following craniotomy, TSSID NPs achieved the best performance in deep-brain angiography among all reported organic 3P materials in terms of vascular imaging depth, signal-to-background ratio, spatial resolution, and hemodynamic imaging depth. Additionally, TSSID NPs demonstrated outstanding biocompatibility through systematic biosafety evaluations. This study provides an excellent imaging agent and useful molecular design philosophy, facilitating the development of advanced organic 3P FLI probes.

The increasing prevalence of methicillin-resistant Staphylococcus aureus (MRSA) due to antibiotic misuse necessitates novel therapeutic strategies to counter multidrug-resistant infections. Here, we introduce a self-assembling, aggregation-enhanced tetrahedral DNA nanostructure (tFNA) platform that achieves targeted drug delivery through controlled aggregation and sustained release, effectively restoring MRSA susceptibility to β-lactam antibiotics. These tetrahedral frameworks, termed tFNAs-ASOs-ceftriaxone sodium (TACs), serve as a dual-functional system that co-encapsulates antisense oligonucleotides (ASOs) targeting the mecA gene and the β-lactam antibiotic ceftriaxone sodium (Cef). Aggregation of TACs plays a pivotal role in maximizing drug retention and stability, prolonging the localized release of both ASOs and antibiotics while maintaining high bioavailability at the infection site. Characterization studies, including size distribution, zeta potential, and fluorescence quenching assays, confirm their robust aggregation stability and encapsulation efficiency, ensuring controlled drug kinetics and prolonged therapeutic effects. Upon interaction with bacterial cells, the locally concentrated TACs facilitate efficient ASO-mediated mecA silencing, thereby disrupting PBP2a expression and re-sensitizing MRSA to β-lactams. Simultaneously, the aggregated ceftriaxone sodium reservoir ensures sustained inhibition of bacterial cell wall synthesis, leading to effective bacterial clearance. In addition, TACs display potent antibiofilm activity by penetrating the biofilm matrix and delivering therapeutics directly to the embedded bacterial population, thereby overcoming the diffusion barriers. In vivo, TACs exhibit superior therapeutic efficacy in an MRSA-induced pneumonia mouse model, significantly improving survival rates, reducing bacterial burden, and mitigating lung tissue damage. These findings highlight the transformative potential of tFNAs as an intelligent drug aggregation and release system, offering a novel paradigm for optimizing antibiotic therapy against multidrug-resistant pathogens.

Active learning (AL) is a powerful method for accelerating novel materials discovery but faces huge challenges for extracting physical meaning. Herein, we novelly apply an interpretable AL strategy to efficiently optimize the photothermal conversion efficiency (PCE) of carbon dots (CDs) in photothermal therapy (PTT). An equivalent value (SHapley Additive exPlanations equivalent value [SHAP-EV]) is proposed which explicitly quantifies the linear contributions of experimental variables to the PCE, derived from the joint SHAP values. The SHAP-EV, with an R² of 0.960 correlated to feature's joint SHAP, is integrated into the AL utility functions to enhance evaluation efficiency during optimization. Using this approach, we successfully synthesized iron-doped CDs (Fe-CDs) with PCE exceeding 78.7% after only 16 experimental trials over four iterations. This achievement significantly advances the previously low PCE values typically reported for CDs. Furthermore, Fe-CDs demonstrated multienzyme-like activities, which could respond to the tumor microenvironment (TME). In vitro and in vivo experiments demonstrate that Fe-CDs could enhance ferroptosis through synergistic PTT and chemodynamic therapy (CDT), thereby achieving remarkable antitumor efficacy. Our interpretable AL strategy offers new insights for accelerating bio-functional materials development in antitumor treatments.

Despite advancements in immune checkpoint blockade (ICB) therapies for treating various tumors, the immunosuppressive environment in oral squamous cell carcinoma (OSCC) significantly limits therapeutic efficacy. Tumor vaccines, which offer great potential for cancer immunotherapy, still face challenges like potential mutation risks, rapid elimination, and low in vivo delivery efficiency. In this study, we fabricate an immunostimulatory nanovaccine using tetrahedral framework nucleic acids (tFNAs) as a carrier for stable and efficient delivery of CpG oligonucleotide. Then an intensive tumor immunotherapeutic strategy by combining tFNA-CpG nanovaccine with PD-1 inhibitor is used in OSCC tumor-bearing mice. Intravenous administration of the tFNA-CpG nanovaccine effectively activates the antigen-presenting cells (APCs), resulting in an increased proportion of M1-like macrophages and mature dendritic cells, accompanied by heightened production of inflammatory cytokines IL-1β, IL-12, and IL-6. When combined with ICB therapy, the anti-PD-1 drug inhibits the PD-1/PD-L1 interaction within tumor microenvironment. Subsequently, the APCs activated by tFNA-CpG facilitate the phenotypic differentiation of T cells, resulting in a substantial boost in infiltration of cytotoxic T cells (expressing IFN-γ and Granzyme B) in both lymph nodes and tumor tissues, thereby executing a potent antitumor effect and inhibiting the progression of OSCC tumors in C3H mouse. Therefore, this study presents an attractive approach to overcoming current ICB limitations in OSCC immunotherapy and provides new avenues for future clinical practice.

Sonodynamic therapy (SDT) has emerged as an advanced technology for treatment of malignant tumors. Many organic and inorganic sonosensitizers have been reported but they still have the respective limitations. Constructing the materials to integrate the superiorities of organic and inorganic sonosensitizers is expected to be a good method to enhance the efficiency of SDT. Herein, we report an intelligent sonosensitizer (TPA–OS⊂CP5@CeO_x), integrating the organic (TPA–OS) and inorganic sonosensitizers (CP5@CeO_x) via host–guest interaction. The modification of carboxyl-pillar[5]arene (CP5) on CeO_x constructs the supramolecular interface by coupling of CP5 and oxygen vacancies. The band gap of CeO_x is reduced and the ratio of Ce⁴⁺/Ce³⁺ is increased to regulate tumor microenvironment. Thus, the SDT performance of CP5@CeO_x can be improved. Furthermore, the synergistic effect of TPA–OS with aggregation-induced emission can further regulate and enhance the SDT efficiency. The cellular experiments demonstrate that TPA–OS⊂CP5@CeO_x exhibits the synergistic therapeutic effect in double organelle of lysosome and mitochondria. The in vivo experiments suggest TPA–OS⊂CP5@CeO_x has imaging-guided enhanced SDT performance to achieve tumor inhibition. This study contributes to the construction of novel intelligent sonosensitizers, indicating that supramolecular interface engineering is promising to realize the customized treatments with minimal side effects.

Aggregation-induced emission (AIE) molecules have attracted widespread attention due to their remarkable fluorescence properties in the aggregated state. However, the highly twisted structures of AIE molecules significantly disrupt the π-conjugations, thus resulting in weak absorption abilities (i.e., small molar absorption coefficients ε). To overcome this problem, herein we have proposed an efficient molecular design strategy: π-bridged dimer of AIE molecules. Accordingly, two series of AIE dimer molecules, TPE-BTO-Dimer 1‒6 and DTPE-BTO-Dimer 1‒6 with various π-bridged moieties, have been newly synthesized. In comparison to the corresponding AIE monomer molecules TPE-BTO and DTPE-BTO, the dimer molecules retain the AIE character while exhibit largely improved absorption abilities (the ε values are increased by 2.3‒3.7 times to 6.01‒9.54 × 10⁴ M⁻¹ cm⁻¹) as well as significantly redshifted absorption maxima. The theoretical calculations have revealed that the π-bridged dimer strategy dramatically increases the oscillator strength of electron transition from the ground state to an excited state and thus results in a large ε. In the transient absorption studies, the local excited state components of dimer molecules are obviously higher than those of monomer molecules, which further confirms the effectiveness of π-bridged dimer strategy. Moreover, one of the AIE dimer molecules DTPE-BTO-Dimer 6 with near-infrared (NIR) emission has been applied in NIR fluorescence imaging-guided photothermal therapy. The very strong absorption ability has enabled its nanoparticles to exhibit a high photothermal conversion efficiency of 73% under the 655 nm laser irradiation and thus display a desired photothermal therapy performance.

Circularly polarized luminescence (CPL) materials are essential for advanced optoelectronic applications, yet efficient chiral design strategies remain challenging. Axial chirality has been widely employed in the construction of CPL materials due to its unique rigid structure. However, the focus has been primarily on the derivatives of carbon–carbon axial chirality. We herein propose a strategy for constructing carbon–nitrogen (C─N) axially chiral molecular frameworks to fully exploit the excellent chromophoric properties of nitrogen-containing heterocycles (such as carbazole). A pair of chiral emitters, (S/R)-AI-2TCFC, was designed and synthesized, exhibiting an emission peak at 578 nm both in the toluene solution and in the neat film state. It possessed typical aggregation-induced emission (AIE), thermally activated delayed fluorescence (TADF), and a luminescence dissymmetry factor (g_lum) of 10⁻³, demonstrating its potential for high-performance device applications. These materials were successfully applied in circularly polarized organic light-emitting diodes (CP-OLEDs), demonstrating promising electroluminescence performance. This innovative strategy not only expands the design toolbox for CPL materials but also paves the way for next-generation high-performance optoelectronic devices.

The emergence of nonconventional luminescent materials (NLMs) has attracted significant attention due to their sustainable synthesis and tunable optical properties. Yet, establishing a clear structure–emission relationship remains a challenge. In this work, we report a previously unknown class of NLMs: cross-linked protein crystals that exhibit intense photoluminescence (PL) in the visible range (425–680 nm). We systematically investigated seven natural protein crystals (concanavalin, catalase, lysozyme, hemoglobin, α-chymotrypsin, pepsin, and β-lactoglobulin) cross-linked with glutaraldehyde and demonstrated that cross-linking induces broadband emission that is absent in natural crystals. Focusing on polymorphic lysozyme crystals (tetragonal, orthorhombic, and monoclinic), we found excitation-dependent fluorescence with lifetimes in the nanosecond range and quantum yields up to 20% (in the monoclinic phase under 450 nm excitation). Single- and two-photon spectroscopy, as well as pressure- and solvent-modulated PL studies, confirm that the emission is due to intermolecular through-space interactions (TSI) within the crystal lattice. Compression enhances TSI and redshifts the emission, whereas the solvent (DMSO)-induced swelling reduces TSI and causes a blue shift, establishing a direct structure–emission correlation. This work establishes protein crystals as programmable NLMs with tunable emission and provides a mechanistic framework for the design of nonconventional luminogens through protein crystal engineering.

Ultralong organic phosphorescence (UOP) materials have garnered significant interest for applications in advanced optical recording and information encryption. However, it remains a formidable challenge achieving manipulated phosphorescence due to the limited color channels and poorly populated triplet energy levels. Herein, we report a novel multiresponsive organic phosphorescence material, in which the phosphorescence color can be dynamically tuned with stimuli such as radiation duration, concentration, excitation wavelength, time, and temperature. The material is based on the confined 7H-benzo[c]carbazole (BCz) molecules in the polymer matrix, which is achieved through the size-dependent cluster-triggered emission (CTE) mechanism. The BCz molecules form isolated molecules and different-sized clusters in the matrix, resulting in multiple luminescent centers with different energy levels and phosphorescence lifetimes. Through matrix confinement effects, the activation states of the monomers and multiple clusters could be precisely modulated, resulting in temperature-controlled tunable orange-to-green variations. Furthermore, the multiresponsive properties of the material have been used in both civil and military applications through sophisticated mathematical modeling. This work potentially proposes a guiding strategy for the development of multiresponsive UOP materials based on CTE molecules.

Nucleotide repeat expansions contribute to the development of a number of neurodegenerative diseases. Recent studies revealed that DNA sequences with CAG and other nucleotide repeat expansions can undergo bidirectional transcription, and the ensuing transcripts could be translated into proteins through repeat-associated non-AUG (RAN) translation; however, not much is known about the precise mechanisms underlying RAN translation. Here, we demonstrated that m⁶A, installed by METTL3 and removed by FTO, promotes RAN translation in all three reading frames from the expanded CAG repeat RNA derived from the human ATXN3 gene, in which repeat expansion contributes to spinocerebellar ataxia type 3 (SCA3). Genetic depletion and pharmacological inhibition of METTL3 result in significantly diminished levels of RAN translation products from all three reading frames, which could be restored by ectopic expression of wildtype METTL3, but not its catalytically inactive mutant. Conversely, genetic ablation of FTO led to augmented RAN translation in all three reading frames. Moreover, one of the RAN translation products, poly(serine), exhibits gel-like aggregates in cells. Together, our study unveiled a crucial role of m⁶A in modulating RAN translation from expanded CAG repeat RNA transcribed from the human ATXN3 gene, and documented new biophysical properties of the poly(serine) RAN translation product.

The healing of diabetic wounds is primarily hindered by persistent inflammation and excessive oxidative stress, increasing the risks of amputation and sepsis. Strategies based on bioactive substances, including recombinant growth factors and histatin proteins (Hsts), have been shown to promote skin-related cell migration, anti-inflammation, angiogenesis, and collagen deposition; however, their long-term stability remains a challenge. Herein, a platelet membrane-coated nanoparticle (PNP) system is proposed to achieve enhanced retention of aggregation-induced emissive (AIE) molecular-modified Hst1 (Hst1-AIE@PNPs) for more efficient repair of diabetic wounds. The Hst1-AIE@PNPs can not only protect Hst1 from degradation in the wound microenvironment but also permit visual monitoring of the controlled release of Hst1 through enhanced fluorescence in the enriched site. Combined with the antioxidant and anti-inflammatory properties of Hst1, Hst1-AIE@PNPs can effectively adsorb inflammation-related factors and further promote re-epithelialization and collagen deposition, thus achieving high-quality wound repair. The results highlight the potential of highly stable aggregation-induced-emission-functionalized Hst1 coated with platelet vesicles as a therapeutic platform to promote diabetic wound-related tissue restoration processes.

Diabetic wound healing impairment, a common complication of diabetes, has limited clinical treatment options and poor therapeutic outcomes, causing significant physical pain and psychological burden for patients. This study aims to accelerate wound healing by modulating cellular stress responses, offering a safe and efficient new therapeutic strategy. Herein, a selenium-containing polyurethane (SePU) thermo-sensitive hydrogel was synthesized, and its mechanism for promoting diabetic wound healing by activating the unfolded protein response (UPR) was elucidated. Hydroxybutyl chitosan (HBC) offers a more convenient application for SePU, with its high hydroxybutyl substitution enabling the hydrogel to undergo a rapid sol–gel transition at physiological temperatures. In vitro experiments showed that SePU thermo-sensitive hydrogel (SePU/HBC), at appropriate concentrations, significantly promoted the proliferation, spreading, migration, and adhesion of human skin fibroblasts (HSFs), while inhibiting inflammation. In vivo diabetic mouse model, SePU/HBC exhibited a significant wound-healing effect, promoting re-epithelialization, collagen formation and maturation. Mechanistic studies revealed that SePU/HBC alleviated endoplasmic reticulum stress under hyperglycemic conditions by activating the UPR-related gene ATF6 to alleviate endoplasmic reticulum stress (ERS) and inhibit apoptosis. This study offers a novel strategy for diabetic wound treatment using SePU/HBC, which activates the UPR and inhibits apoptosis, demonstrating promising clinical applications for wound healing.

In recent years, the exploration of emission pathways from high-excited states in organic luminogens has received extensive attention owing to the anti-Kasha's rule emission with the potential of improving the exciton utilization. However, it is extremely difficult to predict the anti-Kasha effect and estimate the luminescent mechanism of high-energy excited states. We here present a rational design on the basis of the intermolecular noncovalent interactions to achieve the purpose of altering the molecular optoelectronic properties and regulating the distribution of high-energy excited state. The emitter, p-Py-SO₂-DMAC, with π–π dimer stacking is designed and synthesized, which not only exceptionally shows five aggregation morphologies and presents the infrequent aggregation-induced anti-Kasha's rule emission, room-temperature phosphorescence (RTP), and mechanoluminescence (ML) behaviors simultaneously, but also possesses the features of thermally activated delayed fluorescence (TADF) and aggregation-induced emission (AIE). The multiple luminescent mechanisms have been scientifically verified by experimental and theoretical investigations.

More than a century ago, it was known that the accumulation of ordered protein aggregates, amyloid fibrils, accompanies several serious and still largely incurable pathologies, including Alzheimer's and Parkinson's diseases. The striking gap between decades of research identifying amyloids as one of the key drivers of neurodegeneration and the persistent lack of effective anti-amyloid therapies reveals a perplexing contradiction, which we define as the “amyloid paradox.” To address this paradox, here we summarize and analyze current perspectives on the unique properties and pathogenic mechanisms of amyloids, highlighting the variability and complexity of their biological consequences and uncovering the risks and limitations encountered in combating these aggregates. We conceptualize amyloid fibril pathogenicity as a complex cascade extending well beyond direct cytotoxicity, such as that arising from disruption of membranes and other cellular organelles. This review encompasses amyloids' disruptive effects on cellular processes and ability to trigger inflammatory responses, their resistance to degradation, capacity to regenerate after apparent destruction, tendency to propagate throughout the organism, propensity to cytotoxicity-increasing transformation, and ability to sequester and pathologically modify essential biomolecules. This integrated analysis reveals why single-target therapeutic approaches often fail and suggests that effective anti-amyloid strategies must address multiple aspects of amyloid pathogenicity simultaneously. The conceptual reframing of the threats of amyloid fibrils helps explain the origins of the amyloid paradox, enhances our understanding of these complex pathogenic agents, and provides a foundation for developing more effective and safe therapeutic strategies for neurodegenerative diseases. These strategies should address the complex and interconnected nature of amyloid pathogenicity rather than its targeting isolated aspects.