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The development of potent antibiotic alternatives with rapid bactericidal properties is of great importance in addressing the current antibiotic crisis. One representative example is the topical delivery of predatory bacteria to treat ocular bacterial infections. However, there is a lack of suitable methods for the delivery of predatory bacteria into ocular tissue. This work introduces cryomicroneedles (cryoMN) for the ocular delivery of predatory Bdellovibrio bacteriovorus (B. bacteriovorus) bacteria. The cryoMN patches are prepared by freezing B. bacteriovorus containing a cryoprotectant medium in a microneedle template. The viability of B. bacteriovorus in cryoMNs remains above 80% as found in long‐term storage studies, and they successfully impede the growth of gram‐negative bacteria in vitro or in a rodent eye infection model. The infection is significantly relieved by nearly six times through 2.5 days of treatment without substantial effects on the cornea thickness and morphology. This approach represents the safe and efficient delivery of new class of antimicrobial armamentarium to otherwise impermeable ocular surface and opens up new avenues for the treatment of ocular surface disorders. This report introduces a cryo‐delivery platform inside which the predation ability of Bdellovibrio bacteriovorus is highly reserved to impede the development of gram‐negative infections.

Combinational immunotherapy of dendritic cell (DC) vaccines and anti‐programmed cell death protein 1 antibodies (aPD1) has been regarded as a promising strategy for cancer treatment because it not only induces tumor‐specific T cell immune responses, but also prevents failure of T cell functions by the immune suppressive milieu of tumors. Microneedles have emerged as an innovative platform for efficient transdermal immunotherapies. However, co‐delivery of DC vaccines and aPD1 via microneedles has not been studied since conventional microneedle platforms are unsuitable for fragile therapeutics like living cells and antibodies. This study employs our newly invented cryomicroneedles (cryoMNs) to co‐deliver DC vaccines and aPD1 for the combinational immunotherapy. CryoMNs are fabricated by stepwise cryogenic micromoulding of cryogenic medium with pre‐suspended DCs and aPD1, which are further integrated with a homemade handle for convenient application. The viability of DCs in cryoMNs remains above 85%. CryoMNs are mechanically strong enough to insert into porcine and mouse skin, successfully releasing DCs and aPD1 inside skin tissue after melting. Co‐delivery of ovalbumin (OVA)‐pulsed DCs (OVA‐DCs) and aPD1 via cryoMNs induced higher antigen‐specific cellular immune responses compared with the mono‐delivery of OVA‐DCs or aPD1. Finally, administration with cryoMNs co‐encapsulated with OVA‐DCs and aPD1 increases the infiltration of effector T cells in the tumor, resulting in stronger anti‐tumor therapeutic efficacy in both prophylactic and therapeutic melanoma models compared with administration with cryoMNs loaded with OVA‐DCs or aPD1. This study demonstrates the great potential of cryoMNs as a co‐delivery system of therapeutic cells and biomacromolecules for combinational therapies.

Tumor metabolite regulation is intricately linked to cancer progression. Because lactate is a characteristic metabolite of the tumor microenvironment (TME), it supports tumor progression and drives immunosuppression. In this study, we presented a strategy for antitumor therapy by developing a nanogold-engineered Rhodospirillum rubrum (R.r-Au) that consumed lactate and produced hydrogen for optical biotherapy. We leveraged a cryogenic micromolding approach to construct a transdermal therapeutic cryomicroneedles (CryoMNs) patch integrated with R.r-Au to efficiently deliver living bacterial drugs. Our long-term storage studies revealed that the viability of R.r-Au in CryoMNs remained above 90%. We found that the CryoMNs patch was mechanically strong and could be inserted into mouse skin. In addition, it rapidly dissolved after administering bacterial drugs and did not produce by-products. Under laser irradiation, R.r-Au effectively enhanced electron transfer through Au NPs actuation into the photosynthetic system of R. rubrum and enlarged lactate consumption and hydrogen production, thus leading to an improved tumor immune activation. Our study demonstrated the potential of CryoMNs-R.r-Au patch as a minimally invasive in situ delivery approach for living bacterial drugs. This research opens up new avenues for nanoengineering bacteria to transform tumor metabolites into effective substances for tumor optical biotherapy. CryoMNs-R.r-Au employing cryomicroneedles for transdermal delivery of nanogold-engineered Rhodospirillum rubrum through optical biotherapy for remodeling the tumor microenvironment. Under laser irradiation, R.r-Au can effectively enhance lactate consumption and hydrogen production by photochemical transform through electron transfer into the photosynthetic system of R. rubrum, leading to an improved antitumor immune activation. [Display omitted] •The strategy of “charging” bacteria with a nano-materials is to boost the intracellular metabolism of matter and energy using the photosynthetic electron transport chain of R. rubrum to achieve photochemical transformation.•R.r-Au enlarged lactate consumption and hydrogen production through electron transfer into the photosynthetic system of R. rubrum under laser irradiation to improved tumor immune activation for tumor optical biotherapy.•The transdermal therapeutic cryomicroneedles patch as a minimally invasive delivery approach is employed to achieve safe and high-efficiency in situ microactive drug delivery, significantly improving drug bioavailability.

Biotherapy offers a promising approach for treating a variety of diseases. However, the lack of advanced delivery systems remains a significant barrier to improve the efficacy, safety, and cost‐effectiveness of biotherapeutics. The microneedle, as a minimally invasive drug delivery tool, has demonstrated considerable potential in biotherapeutic applications. Despite this promise, challenges remain in fabricating microneedles that effectively preserve the bioactivity of biotherapeutics. Emerging as a novel solution, cryomicroneedles (cryoMNs) employ cryogenically molded ice matrices that exploit phase‐transition thermodynamics. The metabolic stasis induced by cryoimmobilization preserves biomolecular conformation and cellular viability. Moreover, the ice‐reinforced architectures achieve an optimal balance between mechanical penetration capacity and post‐insertion dissolution kinetics, overcoming the rigidity‐flexibility trade‐off in traditional dissolving microneedles. Current research prioritizes three breakthrough directions: material innovation for cryocompatible polymer‐ice interfaces, cold‐chain optimization strategies to enhance payload viability, and innovations in medical application scenarios. Notably, preclinical successes in regenerative tissue engineering and thermostable vaccine platforms highlight cryoMNs’ potential to bridge precision medicine and global health equity. This review provides an overview of recent advancements in cryoMNs and discusses the potential challenges and future directions for the development of cryoMNs‐mediated biotherapeutics delivery. CryoMNs for biotherapeutic delivery to treat various diseases. CryoMNs: cryomicroneedles.