Immunotherapy has revolutionized tumor therapy by harnessing the immune system to selectively get rid of malignant cells [1], [2]. Nonetheless, its scientific efficacy stays constrained by the immunosuppressive tumor microenvironment, which is characterised by inadequate immune infiltration and restricted antigen presentation [3], [4]. To beat these challenges, intensive efforts have been dedicated to reprogramming the tumor microenvironment from an immunologically “chilly” state to an activated “scorching” state, thereby bettering the effectiveness of immunotherapy [5], [6], [7]. Pyroptosis, a pro-inflammatory type of programmed cell loss of life, has emerged as a promising technique for antitumor immune activation. In contrast to apoptosis, which is usually immunologically silent, pyroptosis is mediated by the activation of Caspase proteins that cleave gasdermin (GSDM) relations, resulting in transmembrane pore formation [8]. This course of ends in cell swelling, membrane rupture, and the next launch of pro-inflammatory cytokines and damage-associated molecular patterns (DAMPs), which promote immune cell infiltration and activation [9]. This inflammatory cascade recruits and prompts immune cells, thereby transforming the immunosuppressive tumor microenvironment to elicit sturdy immune response.
Reactive oxygen species (ROS) are acknowledged as potent inducers of Caspase-3/GSDME-mediated pyroptosis [10], [11], [12]. In comparison with different pyroptosis-inducing methods, similar to chemotherapeutic medication, ROS-based therapies allow spatiotemporal activation of immune response by externally utilized power sources, making them promising for scientific translation [13], [14], [15]. Amongst ROS-based modalities, sonodynamic remedy (SDT) affords key benefits over photodynamic and chemodynamic therapies, together with superior tissue penetration, non-invasive activation, and correct spatial management through ultrasound (US) [16], [17], [18], [19].
Steel-organic frameworks (MOFs) [20], [21], [22], [23], a category of crystalline porous supplies composed of steel clusters interconnected by natural ligands, have appeal to important consideration in biomedical purposes as a result of their tunable porosity, excessive floor space, and versatile performance [24]. By various steel nodes (e.g., Cu²⁺, Fe³⁺, Zn²⁺) and natural linkers (e.g., carboxylates, porphyrins), MOFs may be engineered with tailor-made physicochemical properties for focused drug supply, catalytic remedy, and imaging [25], [26]. Notably, MOFs exhibit distinctive benefits as sonosensitizers [27], [28]. Their porous structure permits environment friendly oxygen adsorption and electron switch, vital for ROS era upon US radiation. Cu-TCPP nanosheet (CuT) is a consultant MOFs the place Cu²⁺ coordinate with 4 carboxyl teams and the porphyrin ring of tetrakis(4-carboxyphenyl)porphyrin (A porphyrin-derived sonosensitizer, TCPP), forming a cross-linked framework [29], [30]. This coordination structure not solely suppresses TCPP aggregation but additionally enhances electron switch and oxygen activation, thereby bettering ROS era effectivity. Moreover, fabrication of CuT into ultrathin 2D nanosheets considerably strengthens oxygen adsorption and cost switch, amplifying singlet oxygen (¹O₂) manufacturing upon US stimulation and enabling sturdy pyroptosis initiation [31], [32]. These structural and purposeful benefits distinguish CuT from conventional sonosensitizers and make it a extremely promising platform for SDT-based immunotherapy [33].
Regardless of the potent bioactivity of CuT, inefficient tumor supply stays a significant bottleneck for therapeutic efficacy [34], [35], [36]. Typical administration routes, together with intravenous (i.v.) and intratumoral (i.t.) injection, steadily endure from speedy clearance, poor tumor retention, off-target accumulation, and burst drug launch, severely limiting ROS era in situ[37], [38], [39]. Subsequently, exact and sustained supply of CuT to tumors is important for unleashing its sonodynamic potential.
Microneedle (MN) know-how supplies a strong answer for localized drug supply by enabling minimally invasive [40], tumor-site-specific administration whereas minimizing systemic publicity [41]. In contrast with conventional supply routes, MN enable exact deposition and extended retention of therapeutics within the tumor microenvironment [42], [43]. Silk fibroin (hereafter known as silk), a biocompatible and biodegradable pure polymer, serves as a really perfect matrix for MN fabrication as a result of its mechanical energy and tunable degradation profile [44], [45], [46]. Silk-based MN patches have been extensively employed in drug supply, tissue regeneration, and vaccine administration [47], [48]. Furthermore, their sturdy construction permits environment friendly pores and skin penetration, additional enhancing their effectiveness as a topical drug supply system for immunotherapy [49], [50].
On this examine, a silk-based MN patch loaded with sonosensitizer CuT (CuT-MN) was developed to attain US-activated pyroptosis induction for sturdy sonodynamic-immunotherapy. CuT was synthesized for environment friendly ROS era upon US irradiation. To additional allow exact activation of sonodynamic immunotherapy, CuT was included into silk-based MN, facilitating environment friendly localized, topical supply, deep tumor penetration, and sustained retention of the sonosensitizer (Scheme 1A). This ensures maximized enrichment of CuT on the tumor web site. Upon US irradiation, CuT catalyzes ROS era to activate the Caspase-3/GSDME pathway to induce environment friendly pyroptosis (Scheme 1B). Importantly, US-activated pyroptosis reduce injury to regular tissues, providing extra exact and enhanced immunotherapy. The CuT-MN technique improves tumor-specific drug retention, boosts immune stimulation, enhances SDT-mediated pyroptosis, and reduces off-target results in comparison with typical intratumoral (i.t.) and i.v. administration. Notably, a single topical administration of CuT-MN generates ample in situ ROS to induce sturdy pyroptosis, highlighting its potential as an on-demand, non-invasive sonodynamic immunotherapy platform.
