Smart hydrothermally responsive microneedle for topical tumor treatment

Unreachable subcutaneous solid tumors, especially relatively deep-seated breast cancer and melanoma, have become one of the most commonly diagnosed malignant carcinomas, with approximately 2.6 million new cases and 0.75 million deaths in 2020 [[1], [2], [3]]. Notably, locoregional therapy has been emphasized with ever increasing significance and effectiveness for the treatments of subcutaneous tumors [4,5], which should be ascribed to its unmatchable advantages over traditional systematic chemotherapy, including negligible systematic toxicity, stable curative effect, minimally invasive operation, as well as flexibility for repeated pinpoint treatment [6]. Encouragingly, numerous bio-engineering-based drug delivery systems have been exploited, such as wafer, microcapsule, electrospun nanofibrous patches, injectable hydrogel and so on [[6], [7], [8], [9], [10], [11]]. Among them, microneedles (MNs) system could pierce into the target lesions in a minimal invasive manner, achieving deep drug delivery with its tunable needle length, which could effectively overcome the low drug penetration and undesirable recurrence over other locoregional systems, and simultaneously could perfectly balance patients' comfort, painless and personalized requirements [[12], [13], [14], [15], [16], [17], [18]]. Moreover, MNs systems have created favorable opportunities for the integration of physical therapy (e.g., thermal therapy), which utilizes destructive power to demolish interactive structure upon tumor tissue and accelerate cell apoptosis, allowing for enhanced synergistic treatment, meanwhile making it feasible for responsive on-demand drug delivery, therefore is considered as one of the most promising subcategories for clinical translation severing as preferable pre-operation conversion to maximize surgical benefits or effective post-surgery intervention to prolong patients' survival [[19], [20], [21]].

Currently, photothermal transition induced by near infrared ray (NIR) or laser irradiation is the mainstream strategy for triggering thermal responsive and synergistic treatment of MNs systems [[22], [23], [24]]. Nevertheless, there are still several concerns that urgently need further promotion for clinical application. Firstly, it should be noted that photothermal trigger demanding the assistance from specific bulk machines (e.g., laser generator, stable NIR source) would be annoying for pinpoint treatment [25,26], resulting in repeated home-hospital travel or extra expense for instrument purchase, which may scarify patient's comfort and compliance. Secondly, to enhance the optical absorption and photothermal transition efficiency, the introduction of photothermal agents (e.g., gold nanoparticles, MXene) were always necessary, which could raise the material cost and technology difficulties for industrialization, meanwhile may impose the potential risk of biotoxicity [23,27,28]. Additionally, as thermal therapy is potentially destructive [26], further improvements in temporal-spatial controllability are crucial to evite the damage to surrounding normal tissue and satisfy on-demand on/off switches. Furthermore, easy operation and flexible topological adaptation to the irregular lesions should be emphasized, so that smart attachable MNs platforms could achieve intimate interaction with tumor tissue to ensure stable therapeutic effects. All these challenges and requirements encourage the scientists to exploit the next generation of locoregional therapy MNs systems with convenient on-demand actuation, enhanced delivery efficiency, flexible on/off temporal-spatial controllability, easy operation, as well as superior scenario adaptability, to accelerate their clinical translation.

Here, inspired by a self-heating cooking package and innovative biomimetic sting structures [[29], [30], [31]], we proposed and designed a hydrothermally responsive multi-round acturable microneedle (HRMAM) system for synergistic thermal therapy and responsive chemotherapeutic delivery to assist cancer treatment by providing an on-demand and spatial-temporally synergistic profile [19]. Notably, the hydrothermally responsive formulation on the base of the HRMAM systems could be triggered conveniently by water exposure, which is similar to well produced commercialized cooking package used in self-heating hot pot, generating adequate heat to induce devitrification and payload release from polymers (polycaprolactone, PCL) [32], achieving on-demand thermal-activated deep drug delivery [33]. Moreover, the grooved structure on each needle would improve formulation/melt motion directionally to the deeper tumor regions with the help of capillary action (Scheme 1) [34]. Moreover, this engineering-based detachable HRMAM system was divided into three relatively independent segments, allowing for multi-round precise intervention without mutual interference, and concurrently endowing the HRMAM with enhanced geometrical adaptability at the irregular lesions. Further, to facilitate easy operation, a specific applicator compatible perfectly with HRMAM segment was originally designed, which was capable of promoting the tissue adhesion in a smart self-service manner. Impressively, the HRMAM system achieved encouraging tumor growth inhibition of 75.11% and 72.29% in in vivo model of melanomas and breast carcinoma, respectively, much higher than those of other groups receiving traditional treatment, without obvious side effects. Collectively, it was anticipated that the HRMAM system would manifest great promise to combat unreachable and deep-seated subcutaneous tumors, facilitating clinical translation of locoregional therapy products with high efficiency, low toxicity, flexible controllability, temporal-spatial precision, easy operation, as well as patient's painless, comfort and compliance.

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