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Photosystem I from the menB strain of Synechocystis sp. PCC 6803 containing foreign quinones in the A1 sites was used for studying the primary steps of electron transfer by pump-probe femtosecond laser spectroscopy. The free energy gap (− ΔG) of electron transfer between the reduced primary acceptor A0 and the quinones bound in the A1 site varied from 0.12 eV for the low-potential 1,2-diamino-anthraquinone to 0.88 eV for the high-potential 2,3-dichloro-1,4-naphthoquinone, compared to 0.5 eV for the native phylloquinone. It was shown that the kinetics of charge separation between the special pair chlorophyll P700 and the primary acceptor A0 was not affected by quinone substitutions, whereas the rate of A0 → A1 electron transfer was sensitive to the redox-potential of quinones: the decrease of − ΔG by 400 meV compared to the native phylloquinone resulted in a ~ fivefold slowing of the reaction The presence of the asymmetric inverted region in the ΔG dependence of the reaction rate indicates that the electron transfer in photosystem I is controlled by nuclear tunneling and should be treated in terms of quantum electron–phonon interactions. A three-mode implementation of the multiphonon model, which includes modes around 240 cm−1 (large-scale protein vibrations), 930 cm−1 (out-of-plane bending of macrocycles and protein backbone vibrations), and 1600 cm−1 (double bonds vibrations) was applied to rationalize the observed dependence. The modes with a frequency of at least 1600 cm−1 make the predominant contribution to the reorganization energy, while the contribution of the “classical” low-frequency modes is only 4%.

Disease modifying antirheumatic drugs (DMARDs) have improved the prognosis of autoimmune inflammatory arthritides but a large fraction of patients display partial or nonresponsiveness to front‐line DMARDs. Here, an immunoregulatory approach based on sustained joint‐localized release of all‐trans retinoic acid (ATRA), which modulates local immune activation and enhances disease‐protective T cells and leads to systemic disease control is reported. ATRA imprints a unique chromatin landscape in T cells, which is associated with an enhancement in the differentiation of naïve T cells into anti‐inflammatory regulatory T cells (Treg) and suppression of Treg destabilization. Sustained release poly‐(lactic‐co‐glycolic) acid (PLGA)‐based biodegradable microparticles encapsulating ATRA (PLGA‐ATRA MP) are retained in arthritic mouse joints after intra‐articular (IA) injection. IA PLGA‐ATRA MP enhance migratory Treg which in turn reduce inflammation and modify disease in injected and uninjected joints, a phenotype that is also reproduced by IA injection of Treg. PLGA‐ATRA MP reduce proteoglycan loss and bone erosions in the SKG and collagen‐induced arthritis mouse models of autoimmune arthritis. Strikingly, systemic disease modulation by PLGA‐ATRA MP is not associated with generalized immune suppression. PLGA‐ATRA MP have the potential to be developed as a disease modifying agent for autoimmune arthritis. This work reports a new intraarticular drug delivery strategy of a disease‐modifying agent that can promote durable disease remission in autoimmune arthritis. The agent protects joints from inflammation‐mediated damage while avoiding generalized suppression of immunity. The systemic effect is attributed to epigenetic modulation of T cells by the agent, which enhances and stabilizes disease‐protective regulatory T cells (Treg). [Image composed in part using BioRender.]

Pain is a key symptom associated with rheumatoid arthritis (RA) and can persist even in the context of overall disease control by standard‐of‐care disease modifying anti‐rheumatic drugs (DMARDs). Analgesic agents and corticosteroids are often used to supplement DMARDs for pain relief but lack disease modifying properties, and their sustained use carries adverse risks. In this work, we characterized the progression of pain sensitivity in the SKG mouse model of RA and evaluated the potential therapeutic interventions. Male and female SKG mice, after systemic mannan injection, developed a mechanical pain phenotype and joint swelling, with a strong inverse correlation between clinical arthritis scores and pain thresholds. To test potential interventions for pain alleviation, we evaluated all‐trans retinoic acid (ATRA)‐loaded poly(lactic‐co‐glycolic acid) microparticles (ATRA‐PLGA MP) administered via intra‐articular injection, which we have previously demonstrated to be disease‐modifying. The pain and inflammation patterns assessed by the von Frey test and clinical scoring showed ATRA‐PLGA MP monotherapy reduced inflammation and alleviated mechanical allodynia in arthritic SKG mice, an effect that was amplified by combination treatments with standard‐of‐care agents. In early‐stage arthritis, co‐administration with cytotoxic T‐lymphocyte‐associated protein (CTLA)‐4‐Ig, clinically known as abatacept, delayed disease progression and sustained the reduction of mechanical allodynia. In established arthritis, sequential treatment with the corticosteroid dexamethasone (Dex) reduced cumulative disease burden and reduced mechanical allodynia. These findings highlight the potential of combining ATRA‐PLGA MP with standard‐of‐care treatments as a potential strategy to enhance the efficacy and durability of disease modification and pain alleviation for arthritis management.

Lipids constitute a diverse class of molecular regulators with ubiquitous physiological roles in sustaining life. These carbon‐rich compounds are primarily sourced from exogenous sources and may be used directly as structural cellular building blocks or as a substrate for generating signaling mediators to regulate cell behavior. In both of these roles, lipids play a key role in both immune activation and suppression, leading to inflammation and resolution, respectively. The simple yet elegant structural properties of lipids encompassing size, hydrophobicity, and molecular weight enable unique biodistribution profiles that facilitate preferential accumulation in target tissues to modulate relevant immune cell subsets. Thus, the structural and functional properties of lipids can be leveraged to generate new materials as pharmacological agents for potently modulating the immune system. Here, we discuss the properties of three classes of lipids: polyunsaturated fatty acids, short‐chain fatty acids, and lipid adjuvants. We describe their immunoregulatory functions in modulating disease pathogenesis in preclinical models and in human clinical trials. We conclude with an outlook on harnessing the diverse and potent immune modulating properties of lipids for immunoregulation.

Sustained release of vaccine components is a potential method to boost efficacy compared with traditional bolus injection. Here, we show that a biodegradable hyaluronic acid (HA)‐scaffold, termed HA cryogel, mediates sustained antigen and adjuvant release in vivo leading to a durable immune response. Delivery from subcutaneously injected HA cryogels was assessed and a formulation which enhanced the immune response while minimizing the inflammation associated with the foreign body response was identified, termed CpG‐OVA‐HAC2. Dose escalation studies with CpG‐OVA‐HAC2 demonstrated that both the antibody and T cell responses were dose‐dependent and influenced by the competency of neutrophils to perform oxidative burst. In immunodeficient post‐hematopoietic stem cell transplanted mice, immunization with CpG‐OVA‐HAC2 elicited a strong antibody response, three orders of magnitude higher than dose‐matched bolus injection. In a melanoma model, CpG‐OVA‐HAC2 induced dose‐responsive prophylactic protection, slowing the tumor growth rate and enhancing overall survival. Upon rechallenge, none of the mice developed new tumors suggesting the development of robust immunological memory and long‐lasting protection against repeat infections. CpG‐OVA‐HAC2 also enhanced survival in mice with established tumors. The results from this work support the potential for CpG‐OVA‐HAC2 to enhance vaccine delivery.

Disease-modifying antirheumatic drugs (DMARDs) have greatly improved the treatment of rheumatoid arthritis (RA), but strategies to prevent disease onset and recurring flares remain limited. While abatacept (CTLA-4 IgG) can delay RA onset and corticosteroids are used for flare control, the benefit is temporary. We report that combining standard-of-care treatments with a locally administered immunomodulatory agent, termed Agg-CLNP, enhances both disease prevention and flare mitigation. Agg-CLNP consists of polymer nanoparticles conjugated with an immunodominant aggrecan peptide and encapsulate calcitriol. These nanoparticles are optimized for uptake by dendritic cells (DC) in lymph nodes proximal to arthritic joints. In vitro, Agg-CLNP suppressed costimulatory molecules and HLA class II (HLA-2) expression and upregulated CTLA-4 in human monocyte-derived DC from healthy and RA donors. In SKG mice, a T cell-driven RA model, Agg-CLNP combined with CTLA-4 IgG synergistically delayed disease onset and reduced severity. In a dexamethasone (Dex) withdrawal flare model, post-Dex Agg-CLNP treatment reduced flare severity and preserved a regulatory phenotype in DC, while suppressing local pathogenic TH17 cells. Next generation RNA sequencing of lymph node DC revealed Ctla4 upregulation and changes in other immunomodulatory genes linked to flare prevention. These findings highlight Agg-CLNP as a potential therapeutic strategy to address critical unmet needs in RA management.

Neutrophils are essential effector cells for mediating rapid host defense and their insufficiency arising from therapy‐induced side‐effects, termed neutropenia, can lead to immunodeficiency‐associated complications. In autologous hematopoietic stem cell transplantation (HSCT), neutropenia is a complication that limits therapeutic efficacy. Here, we report the development and in vivo evaluation of an injectable, biodegradable hyaluronic acid (HA)‐based scaffold, termed HA cryogel, with myeloid responsive degradation behavior. In mouse models of immune deficiency, we show that the infiltration of functional myeloid‐lineage cells, specifically neutrophils, is essential to mediate HA cryogel degradation. Post‐HSCT neutropenia in recipient mice delayed degradation of HA cryogels by up to 3 weeks. We harnessed the neutrophil‐responsive degradation to sustain the release of granulocyte colony stimulating factor (G‐CSF) from HA cryogels. Sustained release of G‐CSF from HA cryogels enhanced post‐HSCT neutrophil recovery, comparable to pegylated G‐CSF, which, in turn, accelerated cryogel degradation. HA cryogels are a potential approach for enhancing neutrophils and concurrently assessing immune recovery in neutropenic hosts.

Short-chain fatty acids (SCFAs) are major metabolic products of indigestible polysaccharides in the gut and mediate the function of immune cells to facilitate homeostasis. The immunomodulatory effect of SCFAs has been attributed, at least in part, to the epigenetic modulation of immune cells through the inhibition the nucleus-resident enzyme histone deacetylase (HDAC). Among the downstream effects, SCFAs enhance regulatory T cells (T reg ) over inflammatory T helper (Th) cells, including Th17 cells, which can be pathogenic. Here, we characterize the potential of two common SCFAs—butyrate and pentanoate—in modulating differentiation of T cells in vitro. We show that butyrate but not pentanoate exerts a concentration-dependent effect on T reg and Th17 differentiation. Increasing the concentration of butyrate suppresses the Th17-associated RORγtt and IL-17 and increases the expression of T reg -associated FoxP3. To effectively deliver butyrate, encapsulation of butyrate in a liposomal carrier, termed BLIPs, reduced cytotoxicity while maintaining the immunomodulatory effect on T cells. Consistent with these results, butyrate and BLIPs inhibit HDAC and promote a unique chromatin landscape in T cells under conditions that otherwise promote conversion into a pro-inflammatory phenotype. Motif enrichment analysis revealed that butyrate and BLIP-mediated suppression of Th17-associated chromatin accessibility corresponded with a marked decrease in bZIP family transcription factor binding sites. These results support the utility and further evaluation of BLIPs as an immunomodulatory agent for autoimmune disorders that are characterized by chronic inflammation and pathogenic inflammatory T cells. Graphical Abstract

Room temperature, light induced (P700 +-P700) Fourier transform infrared (FTIR) difference spectra have been obtained using photosystem I (PS I) particles from Synechocystis sp. PCC 6803 that are unlabeled, uniformly 2H labeled, and uniformly 15N labeled. Spectra were also obtained for PS I particles that had been extensively washed and incubated in D 2O. Previously, we have found that extensive washing and incubation of PS I samples in D 2O does not alter the (P700 +-P700) FTIR difference spectrum, even with ∼50% proton exchange. This indicates that the P700 binding site is inaccessible to solvent water. Upon uniform 2H labeling of PS I, however, the (P700 +-P700) FTIR difference spectra are considerably altered. From spectra obtained using PS I particles grown in D 2O and H 2O, a ( 1H- 2H) isotope edited double difference spectrum was constructed, and it is shown that all difference bands associated with ester/keto carbonyl modes of the chlorophylls of P700 and P700 + downshift 4–5/1–3 cm −1 upon 2H labeling, respectively. It is also shown that the ester and keto carbonyl modes of the chlorophylls of P700 need not be heterogeneously distributed in frequency. Finally, we find no evidence for the presence of a cysteine mode in our difference spectra. The spectrum obtained using 2H labeled PS I particles indicates that a negative difference band at 1698 cm −1 is associated with at least two species. The observed 15N and 2H induced band shifts strongly support the idea that the two species are the 13 1 keto carbonyl modes of both chlorophylls of P700. We also show that a negative difference band at ∼1639 cm −1 is somewhat modified in intensity, but unaltered in frequency, upon 2H labeling. This indicates that this band is not associated with a strongly hydrogen bonded keto carbonyl mode of one of the chlorophylls of P700.

Immune Engineering In article number 2202720, Nunzio Bottini, Nisarg J. Shah, and co‐workers report the development of microparticles as a new potential therapy for autoimmune arthritis. When injected in inflamed joints, the microparticles slowly biodegrade and release an immunomodulatory agent that strengthens disease‐protective immune cells. In mouse models of disease, the treatment approach protects joints from damage systemically while avoiding generalized immunosuppression.