Bionic intelligent responsive barbed microneedles synergistically remodel the microenvironment for the treatment of refractory pigmentation disorders (melasma).

Clinically refractory melasma remains difficult to treat because it is driven by a multidimensional pathological microenvironment that includes melanocyte hyperactivity, aberrant vascular growth, oxidative stress and chronic inflammation. Single-pathway therapies therefore often produce incomplete or transient responses. To remodel this microenvironment more broadly, we developed a bioinspired, stimulus-responsive co-delivery microneedle platform (TXA/Exo@HAMA-PBA MNs). Inspired by the backward-curved barbs on the tick hypostome, the microneedles were engineered with outward-facing barbs to improve anchoring within skin tissue. Chemically, adipose-derived stem cell exosomes (ADSC-Exos) acted as bioactive crosslinking nodes. They were coupled to the HAMA-PBA matrix through ROS-sensitive dynamic boronate ester bonds, while tranexamic acid (TXA) was physically co-encapsulated. After insertion into ROS-rich melasma-like lesions, oxidative cleavage of carbon-boron bonds accelerated matrix degradation and promoted on-demand release of both payloads. Mechanistically, this platform produced an asymmetric but coordinated blockade of the pathological microenvironment: ADSC-Exos mainly scavenged local ROS, including ·OH, whereas TXA preferentially disrupted abnormal capillary networks. Together, they suppressed melanogenesis through the MITF/TYRP1 cascade and shifted macrophages from a pro-inflammatory M1 phenotype towards a tissue-reparative M2 phenotype. In a UV/progesterone-induced mouse model of melasma validated by bulk RNA sequencing, the system produced multidimensional microenvironmental regulation and visible depigmentation. This bioinspired, spatiotemporally responsive co-delivery microneedle platform integrates complementary and synergistic therapeutic actions and offers a translational strategy for complex, multifactorial hyperpigmentary disorders.