Localized Delivery of a Microneedle Patch Loaded with db-cAMP Promotes Spinal Cord Injury Repair through the CREB/PI3K/AKT Signaling Axis

Haoyun Liu; Yanbing Kao; Binghao Gao; Guangjin Gu; Renjie Zhang; Runhan Fu; Hanming Zhu; Yu Yang; Zhihao Zhang; Shengran Li; Shiqing Feng; Xiaohong Kong

doi:10.1016/j.eng.2026.05.014

Engineering ›› :202605014 DOI: 10.1016/j.eng.2026.05.014

research-article

Localized Delivery of a Microneedle Patch Loaded with db-cAMP Promotes Spinal Cord Injury Repair through the CREB/PI3K/AKT Signaling Axis

Haoyun Liu ^a^,^c^,^#
, Yanbing Kao ^a^,^c^,^#
, Binghao Gao ^a^,^c
, Guangjin Gu ^a^,^c
, Renjie Zhang ^b^,^c
, Runhan Fu ^a^,^c
, Hanming Zhu ^b^,^c
, Yu Yang ^a^,^c
, Zhihao Zhang ^a^,^c
, Shengran Li ^a^,^c
, Shiqing Feng ^a^,^b^,^c^,^*
, Xiaohong Kong ^a^,^c^,^*

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Abstract

Astrocyte polarization into a complement component 3 positive (C3⁺) neurotoxic A1 phenotype is a hallmark of the inflammatory cascade following spinal cord injury (SCI), where it plays a pivotal role in exacerbating neuronal senescence, inhibiting axonal regeneration, and limiting functional recovery. Although cyclic adenosine monophosphate (cAMP) signaling has been implicated in modulating astrocyte activation, the precise molecular pathways regulating C3⁺ astrocyte differentiation and their downstream effects on neuroinflammation remain insufficiently understood. In this study, we identified cAMP response element binding protein (CREB) as a critical regulator of astrocyte polarization. Activation of CREB using dibutyryl-cAMP (db-cAMP), a cell-permeable cAMP analog, led to a 43% reduction in the number of C3⁺ astrocytes and a 15% decrease in C3 protein expression within 24 h in vitro. Functionally, the suppression of neurotoxic astrocytes alleviated neuronal senescence and reshaped the immune microenvironment by reducing classically activated macrophage (M1 macrophage) polarization, enhancing alternatively activated macrophage (M2 macrophage) responses, and promoting efferocytosis. Our transcriptomic profiling and pathway enrichment analyses further revealed that the CREB/phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling axis mediates the anti-inflammatory and neuroprotective reprogramming of astrocytes. We further engineered an adhesive microneedle patch (db-cAMP@MP) capable of sustained, targeted delivery of db-cAMP into the injured spinal cord lesion site to achieve localized therapeutic modulation of astrocyte phenotypes in vivo. The application of db-cAMP@MP following SCI effectively activated CREB signaling in spinal astrocytes, resulting in reduced C3⁺ astrocyte accumulation, decreased neuronal senescence marker expression, and a 1.4-fold increase in motor evoked potential (MEP) amplitude and motor functional recovery, with a Basso Mouse Scale (BMS) score of 3.8 ± 0.83 in the SCI model. Our findings establish CREB as a central molecular switch in astrocyte-driven neuroinflammation and identify db-cAMP@MP as a promising, precision-targeted therapeutic platform to modulate astrocyte phenotypes and promote functional repair after SCI.

Keywords

CREB / Spinal cord injury / Astrocyte / Neuronal senescence / Microneedle patch

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Haoyun Liu, Yanbing Kao, Binghao Gao, Guangjin Gu, Renjie Zhang, Runhan Fu, Hanming Zhu, Yu Yang, Zhihao Zhang, Shengran Li, Shiqing Feng, Xiaohong Kong. Localized Delivery of a Microneedle Patch Loaded with db-cAMP Promotes Spinal Cord Injury Repair through the CREB/PI3K/AKT Signaling Axis. Engineering 202605014 DOI:10.1016/j.eng.2026.05.014

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References

Publishing order | Descend order by publishing year | Descend order by cited within

[1]	Lee HG, Wheeler MA, Quintana FJ . Function and therapeutic value of astrocytes in neurological diseases. Nat Rev Drug Discov 2022; 21(5):339-58.

[2]	Verkhratsky A, Butt A, Li B, Illes P, Zorec R, Semyanov A, et al. Astrocytes in human central nervous system diseases: a frontier for new therapies. Signal Transduct Target Ther 2023; 8(1):396.

[3]	Burda JE, Sofroniew MV . Reactive gliosis and the multicellular response to CNS damage and disease. Neuron 2014; 81(2):229-48.

[4]	Liddelow SA, Guttenplan KA, Clarke LE, Bennett FC, Bohlen CJ, Schirmer L, et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 2017; 541(7638):481—7.

[5]	Chi X, Yin S, Sun Y, Kou L, Zou W, Wang Y, et al. Astrocyte—neuron communication through the complement C3—C3aR pathway in Parkinson’s disease. Brain Behav Immun 2025; 123:229-43.

[6]	Chang J, Qian Z, Wang B, Cao J, Zhang S, Jiang F, et al. Transplantation of A2 type astrocytes promotes neural repair and remyelination after spinal cord injury. Cell Commun Signal 2023; 21(1):37.

[7]	Dinevska M, Widodo SS, Cook L, Stylli SS, Ramsay RG, Mantamadiotis T . CREB: a multifaceted transcriptional regulator of neural and immune function in CNS tumors. Brain Behav Immun 2024; 116:140-9.

[8]	Kao Y, Zhu H, Yang Y, Shen W, Song W, Zhang R, et al. CREB1 facilitates gabaergic neural differentiation of human mesenchymal stem cells through BRN2 for pain alleviation and locomotion recovery after spinal cord injury. Cells 2023; 13(1):67.

[9]	Sun W, Liu Z, Jiang X, Chen MB, Dong H, Liu J, et al. Spatial transcriptomics reveal neuron—astrocyte synergy in long—term memory. Nature 2024; 627(8003):374-81.

[10]	Pardo L, Schlüter A, Valor LM, Barco A, Giralt M, Golbano A, et al. Targeted activation of CREB in reactive astrocytes is neuroprotective in focal acute cortical injury. Glia 2016; 64(5):853-74.

[11]	Liu M, Zhang W, Han S, Zhang D, Zhou X, Guo X, et al. Multifunctional conductive and electrogenic hydrogel repaired spinal cord injury via immunoregulation and enhancement of neuronal differentiation. Adv Mater 2024; 36(21):e2313672.

[12]	Liu J, Yao Z, Hu Z, Zhang X, Gong B, Dai Y, et al. Spatiotemporal delivery of required facilitators for microenvironment remodeling propels neural regeneration after spinal cord injury. Adv Mater 2026; 38(1):e03479.

[13]	Fang A, Wang Y, Guan N, Zuo Y, Lin L, Guo B, et al. Porous microneedle patch with sustained delivery of extracellular vesicles mitigates severe spinal cord injury. Nat Commun 2023; 14(1):4011.

[14]	Kao Y, Song W, Zhang R, Gu G, Qiu H, Shen W, et al. Synergistic restoration of spinal cord injury through hyaluronic acid conjugated hydrogel—polydopamine nanoparticles combined with human mesenchymal stem cell transplantation. Bioact Mater 2025; 46:569-81.

[15]	Song W, Fu R, Yuan Z, Liu Y, Kao Y, Zhang R, et al. Targeting RelA/NLRP3/CCL3 axis mitigates microglia inflammatory response and promotes recovery after spinal cord injury. Brain Behav Immun 2025; 129:801—17.

[16]	Zhou M, Yao X, Huang B, Ren J, Feng H, Feng S . Frontier integration in spinal cord injury repair: engineering—driven mechanistic exploration and a new paradigm for clinical translation. Engineering 2026; 60:310-35.

[17]	Lau BY, Fogerson SM, Walsh RB, Morgan JR . Cyclic AMP promotes axon regeneration, lesion repair and neuronal survival in lampreys after spinal cord injury. Exp Neurol 2013; 250:31-42.

[18]	He X, Li Y, Deng B, Lin A, Zhang G, Ma M, et al. The PI3K/AKT signalling pathway in inflammation, cell death and glial scar formation after traumatic spinal cord injury: mechanisms and therapeutic opportunities. Cell Prolif 2022; 55(9):e13275.

[19]	Egor G, Andrey S, Elena K, Olga B, Elena T, Anton S . The impact of glutamatergic excitotoxicity on the differentiation of cerebellar neural stem cells. J Mol Neurosci 2025; 75(4):129.

[20]	Jimenez Hamann MC, Tsai EC, Tator CH, Shoichet MS . Novel intrathecal delivery system for treatment of spinal cord injury. Exp Neurol 2003; 182(2):300-9.

[21]	Ma W, Li X . Spinal cord injury repair based on drug and cell delivery: from remodeling microenvironment to relay connection formation. Mater Today Bio 2025; 31:101556.

[22]	Li J, Zeng M, Shan H, Tong C . Microneedle patches as drug and vaccine delivery platform. Curr Med Chem 2017; 24(22):2413—22.

[23]	Han M, Yang H, Lu X, Li Y, Liu Z, Li F, et al. Three—dimensional—cultured MSC—derived exosome—hydrogel hybrid microneedle array patch for spinal cord repair. Nano Lett 2022; 22(15):6391-401.

[24]	Zhai X, Chen K, Wei X, Zhang H, Yang H, Jiao K, et al. Microneedle/CD—MOF—mediated transdural controlled release of methylprednisolone sodium succinate after spinal cord injury. J Control Release 2023; 360:236-48.

[25]	Xiao L, Shi K, Li W, Liu J, Xie P, Hu Z, et al. Targeting fibrotic scarring by mechanoregulation of Il11ra1⁺/Itga11⁺ fibroblast patterning promotes axon growth after spinal cord injury. Adv Sci 2025; 12(44):e13476.