EHI ISO 2026_ARPA-H-SOL-26-150_Amendment 1.pdf

ARPA-H-SOL-26-150, EHI

INNOVATIVE SOLUTIONS OPENING

FOR

EMERGING

HEALTH

INNOVATORS

EHI

OFFICE OF COMMERCIALIZATION

ARPA-H-SOL-26-150

September 15, 2026

TABLE OF CONTENTS

1. ISO PURPOSE

1.1 ISO QUESTIONS AND ANSWERS (Q&A)

1.2 DEFINITIONS

2. THE INITIATIVE

2.1 EHI OVERVIEW

2.2 INITIATIVE STRUCTURE, TIMELINE AND TOPICS

2.3 TOPIC AREAS

TOPIC 1: PRECISION CONTROL OF SKIN INFLAMMATION WITHOUT SYSTEMIC EXPOSURE 6

TOPIC 2: INTERNAL SENSING AND TARGETED CONTROL OF INFLAMMATION

TOPIC 3: DEEP BRAIN STIMULATION FOR MECHANISTIC SLEEP EXPLORATION (DEEP

SLEEP)

TOPIC 4: CLEAR-MIND — RESTORING THE BRAIN’S DRAINAGE AND IMMUNE BALANCE TO

ENABLE HEALING AFTER INJURY

TOPIC 5: HOST-PATHWAY INTERVENTIONS FOR NEUROTROPIC DISEASE (HIND)

TOPIC 6: PROTECTING PATIENT DATA IN LIFE SCIENCE AI

TOPIC 7: ENGINEERING DRT FOR PROGRAMMABLE DNA SYNTHESIS AS EMERGING NEW

MEDICAL COUNTERMEASURES (MCM) STRATEGY

TOPIC 8: PREVENTION OF LETHAL ALPHA-GAL ALLERGIC RESPONSES CAUSED

BY TICK BITES

TOPIC 9: SMILE (SMART MICROBIOME-INFORMED LESION & ENAMEL RESTORATION)

TOPIC 10: ENDING PREVENTABLE DEATHS FROM ECTOPIC PREGNANCY THROUGH

FIRST-VISIT DIAGNOSIS

TOPIC 11: TRANSFORMING THE WELL-WOMAN EXAM THROUGH OBJECTIVE DATA . 16

TOPIC 12: INNOVATIONS IN BIOTRANSPORT TO SUPPORT LONG-TERM

PRESERVATION OF TISSUES AND ORGANS

TOPIC 13: ORGANS-IN-ACTION: NEXT-GENERATION HUMAN TISSUE PLATFORMS FOR

LONGEVITY, DISEASE, AND THERAPY DISCOVERY

TOPIC 14: NEAR REAL-TIME, NON-CONTACT DETERMINATION OF STERILITY IN

DISTRIBUTED MANUFACTURING SYSTEMS

TOPIC 15: ICAT (IN-CAVITY ADJUVANT THERAPY): IMPLANTABLE SYSTEMS FOR LOCAL

CANCER CONTROL AT THE RESECTION MARGIN

TOPIC 16: CAUSALLY-GROUNDED ALIGNMENT FOR CLINICAL GENERATIVE ARTIFICIAL

INTELLIGENCE TOOLS

2.4 PROPOSERS

2.5 TENTATIVE EHI PROGRAM MEETINGS AND ATTENDANCE

2.6 ELIGIBILITY INFORMATION

ELIGIBILITY

NON-U.S. ENTITIES

2.7 SYSTEM FOR AWARD MANAGEMENT (SAM)

3. EHI SUBMISSION AND EVALUATION PROCESS

3.1 SUBMISSION PROCESS OVERVIEW

3.2 SOLUTION SUMMARY SUBMISSIONS

3.3 FULL PROPOSAL SUBMISSIONS

3.4 SUBMISSION INFORMATION

3.5 PROPRIETARY INFORMATION

3.6 REVIEW, EVALUATION, AND SELECTION PROCESS FOR AWARD

REVIEW AND EVALUATION TIMELINES

EVALUATION CRITERIA FOR STEP 1 – SOLUTION SUMMARIES

EVALUATION CRITERIA FOR STEP 2 – FULL PROPOSAL AND AWARD

3.7 EVALUATION AND AWARD DISCLAIMERS

4. POLICY REQUIREMENTS AND MISCELLANEOUS OTHER INFORMATION

4.1 CONTROLLED UNCLASSIFIED INFORMATION (CUI) ON NON-FEDERAL

INFORMATION SYSTEMS

4.2 ORGANIZATIONAL CONFLICTS OF INTEREST (OCI)

4.3 AGENCY SUPPLEMENTAL OCI POLICY

4.4 RESEARCH SECURITY DISCLOSURES

4.5 INTELLECTUAL PROPERTY (IP)

4.6 HUMAN SUBJECTS RESEARCH

4.7 ANIMAL SUBJECTS RESEARCH

4.8 ELECTRONIC INVOICING AND PAYMENTS

4.9 GOVERNMENT-FURNISHED PROPERTY/EQUIPMENT/INFORMATION

ATTACHMENT A: Solution Summary Template

ATTACHMENT B: Pitch Slides Template

ATTACHMENT C: Technical and Management Proposal Template

ATTACHMENT D: Task Description Document (TDD)

ATTACHMENT E: Milestone Payment Schedule Template

ATTACHMENT F: Administrative and National Policy Requirements Document Template

ATTACHMENT G: ARPA-H Model Other Transaction (Provided for reference purposes only)

FEDERAL AGENCY: Advanced Research Projects Agency for Health (ARPA-H)

PROGRAM TITLE: Emerging Health Innovators (EHI) Initiative

ANNOUNCEMENT TYPE: Solicitation

ISO SOLICITATION NUMBER: ARPA-H-SOL-26-150

DATES: (All times listed are Eastern Time)

• Solution Summaries Due: October 30, 2026, 2:00 PM ET

• Questions & Answers (Q&A) due date: February 3, 2027, 2:00 PM ET

• Full Proposals Due: February 10, 2027, 2:00 PM ET

• Tentative Performer Selection Date: April 30, 2027

• Tentative Award Start Date: June 30, 2027

ANTICIPATED AWARDS: Multiple Other Transaction (OT) Agreements

AWARD AMOUNT: Each award consists of the following periods of performance and not to ex-ceed (NTE) values. Total Award Value shall not exceed $1,050,000:

o Base Period Year 1 (12 Months): $350,000 (NTE) o Base Period Year 2 (12 Months): $350,000 (NTE) o Option Period Year 3 (12 Months): $350,000 (NTE)

AGENCY CONTACT: All inquiries should be sent to EHI2026@ARPA-H.gov

1. ISO PURPOSE

ARPA-H seeks proposals from all eligible entities (see Section 2.6 Eligibility Information) to ac-complish the EHI Program goals as described in this solicitation package. Ultimately, ARPA-H intends to negotiate multiple OT Agreements with proposers whose proposals are most ad-vantageous to the Government.

1.1 ISO QUESTIONS AND ANSWERS (Q&A)

All questions regarding this Innovative Solutions Opening (ISO) must be submitted to EHI2026@ARPA-H.gov. ARPA-H will post Q&As to the ARPA-H EHI webpage on an ongoing basis and will not respond directly to email inquiries. All questions should be in English and must include the name, email address, telephone number of a point of contact, and should be submitted by the Q&A deadline posted with other key dates. Do not submit questions to indi-vidual Government team members.

ARPA-H will attempt to answer questions in a timely manner; however, questions submitted after the due date may not be answered. Further, duplicative questions may be combined and rephrased to streamline responses.

1.2 DEFINITIONS

Several important terms used within this solicitation are defined below:

mailto:EHI2026@ARPA-H.gov?subject=EHI%20Questions

• Early-Career Investigator – An individual within 8 years of completing their first terminal degree who is eligible to serve as Project Lead (leaves of absence, post-doctoral, resi-dency, and fellowship periods can be excluded for determination of eligibility). Post-doctoral fellows/trainees and clinical trainees do not qualify as Early-Career Investiga-tors for purposes of serving as Project Lead but may participate as support staff.

• Key Member – An individual identified in the proposal (including the project lead and any other named personnel, whether employed by the proposer or a subawardee/con-sultant) whose expertise or role is critical to executing the Task Description Document

(TDD).

• Proposer – A “proposer” is the organization responding to this ISO. Proposers must have a unique entity identifier (UEI) and be registered in SAM.gov to submit a response to this ISO.

• Project Lead – The “project lead” is the individual representative from the proposer’s organization who leads the project’s progress and success.

• Selectee – After a proposer is selected for negotiation of a potential award, they are considered a “selectee.”

• Performer – After a selectee’s agreement has been awarded, they are considered a “per-former.”

• Topic Area (TA) – Indicates one of the multiple technical submission pathways within the EHI Initiative. Proposers will only be permitted to respond to one TA.

2. THE INITIATIVE

2.1 EHI OVERVIEW

Initiative Overview: The EHI Initiative will ensure ARPA-H identifies and engages early career investigators. To achieve this goal, ARPA-H is soliciting proposals from these researchers and innovators and their organizations to develop cutting-edge biomedical, health, and commu-nity-engaged research and innovation.

This ISO solicits proposals that must identify one eligible Project Lead/PI for research and de-velopment in the specific TAs identified in Section 2.3. Teams may include collaborators, subawardees and consultants. Potential applicants are encouraged to carefully consider the descriptions of the TAs before submission. Applicants may not submit to multiple TAs and will be required to choose one TA for a solution summary or proposal submission and identify this TA on the submission’s cover sheet. A submission may be determined to be non-conforming if the solution summaries or proposal does not clearly address a specific TA or an applicant sub-mits more than one solution summary or proposal for consideration. ARPA-H reserves the right to assign a solution summary or proposal to a different topic area than indicated by the pro-poser.

Prior to submitting a proposal, applicants are required to first submit a solution summary. After reviewing a solution summary, ARPA-H will notify the proposer only of a determination to either "encourage" or "discourage" submission of a full proposal. No additional feedback — written or verbal — will be provided at this stage. The project lead should be a researcher, not an ad-ministrator, who meets eligibility criteria as defined in Section 2.6.1.

2.2 INITIATIVE STRUCTURE, TIMELINE AND TOPICS

The EHI program initiative is a mentorship program that seeks to identify and engage with early-career individuals so they can learn about ARPA-H’s approach to addressing gaps in health care in the United States while seeding new and innovative research ideas. The EHI pro-gram will fund innovative research proposals across diverse technical areas of interest to ARPA- H. Further details regarding the specific technical areas of interest are in Section 2.3.

Proposals must cover a 24-month base period and for all research activity. Each proposal must include a plan for an additional 12-month option period called the “Director’s Award”. This op-tional period will be reserved for a limited number of performers who demonstrate exceptional EHI project performance over the 24-month base period.

The EHI program contains multiple TAs. Proposed research should investigate innovative ap-proaches that enable revolutionary advances in science, devices, or systems. Specifically ex-cluded is research that primarily results in evolutionary improvements to the existing state of practice.

2.3 TOPIC AREAS

Topic 1: Precision Control of Skin Inflammation without Systemic Exposure

Autoimmune and inammatory skin diseases (e.g., psoriasis, systemic sclerosis) affect over 7 million Americans and drive approximately $150B in annual healthcare costs, with major pain, disgurement, disability, and systemic comorbidities. Current care relies on topical agents and systemic immunomodulators or biologics that are imprecise, require chronic use, and can cause serious adverse effects. Management is episodic and reactive, with no continuous sensing of local immune status. No existing technology provides intelligent, persistent skin-surface biosen-sor networks that sense cutaneous inammation and autonomously modulate therapy while preventing systemic exposure. These limitations constrain precise, surface-level, adaptive con-trol of skin inammation and perpetuate reliance on systemic immunosuppression.

ARPA-H seeks bold, cross-disciplinary solutions that integrate biomaterials, AI/swarm network-ing, and immunomodulation to enable precise, surface-level, adaptive control of skin inamma-tion without systemic immunosuppression. ARPA-H is particularly interested in networked, non-internalizable biomaterials that reside in supercial skin layers, self-organize to sense cutaneous inammation, share data, and deliver localized treatment or defer treatment when systemic risk is high. Concepts that exclude systemic, lymphatic, and neural uptake while enabling distributed sensing, computation, and reversible therapy conned to the skin are especially encouraged.

Proposed concepts may encompass innovations in techniques, platforms, and/or integrated technologies that:

• Achieve persistent, surface-level biosensing of local immune status across supercial skin layers, with validated exclusion from systemic, lymphatic, and neural compartments

• Enable self-organizing network behavior among distributed biomaterial elements to share data, perform local computation, and coordinate reversible, localized therapy

• Establish treatment logic that delivers localized intervention during inammatory ares or defers therapy when systemic risk is high, tailored to specic cutaneous autoimmune and inammatory indications (e.g., psoriasis, systemic sclerosis)

Concepts should be supported by clear experimental or computational strategies to demon-strate feasibility and rigor, such as:

• Platform demonstrations with validated systemic exclusion and core sensing/network-ing functions in early phases

• Integrated prototypes with dened performance in relevant preclinical models at mid-program milestones

• Rigorous safety/biocompatibility assays, independent validation, and robust encryp-tion/cybersecurity testing of network logic

Robust metrics for technical performance (e.g., sensing accuracy, network stability, systemic safety, treatment efficacy, biocompatibility), impact, operability (including ease of application/re-moval, comfort, and integration into dermatology workows), cost and manufacturability for out-patient and home use, and commercialization potential are expected.

Topic 2: Internal Sensing and Targeted Control of Inflammation

Inammatory diseases affect over 100 million Americans and cost hundreds of billions of dollars annually. Current anti-inammatory therapies are imprecise, can cause systemic toxicity even for localized disease, and require repeat clinical visits. Care is reactive and based on intermittent data, with major gaps in internal real-time inammatory sensing, coordination of multi-site in-ammation via injectable or ingestible platforms, and micro-/nano-scale closed-loop or exter-nally controlled therapy. As a result, millions of patients continue to receive whole-body drugs that cause signicant side effects, while inammation at its source remains poorly characterized and inadequately controlled.

ARPA-H seeks cross-disciplinary solutions that integrate nanotechnology, immunomodulation, and AI/swarm networking to enable precise, autonomous inammation control that treats dis-ease at its source while sparing healthy tissue. We are particularly interested in injectable or in-gestible micro/nano-scale networked platforms that reside in the body, sense inammation, and deliver targeted therapy under external or closed-loop control. Concepts that leverage biocom-patible micro/nanoparticles for tissue-targeted platforms, miniaturized inammatory biosen-sors, swarm-inspired signaling protocols, and externally triggered or closed-loop drug delivery are especially encouraged.

• Achieve internal, real-time sensing of inammation via injectable or ingestible mi-cro/nano-scale platforms with validated biocompatibility and durability

• Enable cross-tissue communication and coordination across multi-site inammation through swarm signaling and/or externally controlled therapy with validated safety

• Establish closed-loop or externally triggered drug delivery with overrides and fail-safes, tunable to specic inammatory conditions and anatomical sites

Concepts should be supported by clear experimental and computational strategies to demon-strate feasibility and rigor, such as:

• Platform demonstrations with validated systemic exclusion and core sensing/network-ing functions in early phases

• Integrated prototypes with dened performance in relevant preclinical models at mid-program milestones

• Simulation-guided, iterative in vivo testing, parallel materials evaluation, and rigorous preclinical safety studies

Robust metrics for technical performance (e.g., sensing accuracy, cross-tissue communication delity, biocompatibility, durability, safe degradation/clearance, therapeutic efficacy), impact, operability (including delivery via standard injection or ingestion for use in primary care and rural settings), cost and manufacturability benchmarked against biologics, and commercializa-tion potential are expected.

Topic 3: Deep Brain Stimulation for Mechanistic Sleep Exploration (Deep Sleep)

Sleep is a critical driver of cognition, mental health, and overall physiological resilience, yet most human sleep research is constrained to supercial measures such as scalp electroencephalo-gram (EEG), wearables, and subjective reports. These approaches provide only coarse views of neural dynamics and offer limited insight into how deep-brain circuits orchestrate and modulate sleep quality. As a result, the mechanisms linking specic deep-brain activity patterns during sleep to physical health, mental health, and neurodegeneration remain poorly understood, and opportunities for precise, circuit-level interventions are largely unexplored.

Implantable deep brain stimulation (DBS) technologies offer the potential to directly sense and perturb neural activity in deep structures during sleep. DBS systems provide an opportunity to both monitor and modulate deep brain structures and circuits to identify intracranial biomarkers of sleep-wake dynamics and advance therapeutic innovations for improving sleep quality.

ARPA-H is interested in understanding activity in deep brain circuits during sleep with the aim of unlocking new treatments to optimize sleep quality. This topic seeks approaches that leverage DBS technologies to: (1) measure and characterize deep brain electrophysiological activity that control arousal and sleep-wake dynamics; (2) quantify how these signals correlate with super-cial cortical activity and other physiological markers; (3) establish causal relationships via tar-geted, closed-loop modulation during sleep; and/or (4) advance novel closed-loop, personal-ized interventions that modulate the deep brain circuits of arousal and sleep.

Topic 4: CLEAR-MIND — Restoring the Brain’s Drainage and Immune Balance to Enable Healing After Injury

The brain glymphatic system and the immune system play key roles in resolving damage to the brain due to trauma, surgery, or other insults. The immune system can be suppressed, either chronically (e.g. patients with organ transplants, auto-immunity, etc.) or acutely (e.g. to control inammation during surgery or after other forms of injury). This immune suppression, however, can be counterproductive by interfering with glymphatic function in the brain, which is essential for healing.

This topic seeks to develop interventions that restore the brain’s natural drainage and rebalance its immune response after injury, so that the effects of the initial insult are not exacerbated.

ARPA-H is interested in treating these two systems — drainage and immunity — as something that can be measured and restored, rather than left to fail. Proposers are encouraged to show, in preclinical models, that re-establishing the brain’s drainage and calming the harmful aspects of its immune response leads to measurable improvements in outcome.

This is a hard, cross-disciplinary problem that no single field or company is positioned to solve alone. It requires bringing together experts in the brain’s vascular and lymphatic systems, the immune system, imaging, and targeted therapeutic delivery. A central challenge is timing: the brain’s immune cells can be both helpful and harmful at different times post-injury, so any inter-vention must be delivered in the right window. Proposers are encouraged to address this timing directly and to use imaging that can track drainage and inflammation over time.

Given the level of effort, this topic is scoped as a mechanistic feasibility effort, not a cure. The goal is to prove that drainage can be restored in the context of immune system modulation, shifting the immune response toward repair, and providing real signs of improved outcomes — packaged as a go/no-go evidence base for a larger program. Restoring function for the millions living with brain-injury disability is the long-term vision; this effort takes the first rigorous step. It is well-suited to an early-career investigator working across brain science, immunology, and bi-oengineering.

Performers will be asked 1) to demonstrate a model of immune suppression that worsens glym-phatic function and outcomes in response to brain damage (year 1); 2) identify target pathways for intervention (year 2); and 3) test selected interventions (year 3).

Quantifiable objectives (24-month feasibility):

• Restore ≥ 50% of normal brain drainage (measured by imaging) after injury in a preclinical model undergoing immune suppression

• Demonstrate a measurable shift in immune cells from a damaging to a repair-supporting state

• Achieve a ≥ 30% reduction in injury and inflammation markers versus untreated controls

• Deliver a go/no-go evidence package linking restored drainage and immune balance to improved outcomes

Topic 5: Host-Pathway Interventions for Neurotropic Disease (HIND)

Neurotropic pathogens such as rabies virus and Eastern equine encephalitis virus along with prion-associated disorders remain extraordinarily difficult to treat once neurologic symptoms emerge. In many cases, pathogen-directed strategies, such as monoclonal antibodies, are too slow, incomplete, or biologically insufficient to prevent progressive CNS injury after disease is clinically apparent. As a result, patients often face irreversible neurologic decline, with few or no options beyond supportive care.

ARPA-H is interested in research concepts that address the central problem of whether late-stage neurotropic disease can still be therapeutically altered by interrupting host or host-path-ogen processes that drive ongoing pathology after CNS involvement. Relevant processes may include maladaptive neuroimmune activation, neuronal injury or degeneration programs, bar-rier dysfunction, synaptic or circuit destabilization, metabolic failure, proteostatic collapse, or other disease-amplifying host responses.

Projects should focus on clinically relevant symptomatic stages and seek to determine whether manipulation of these processes can preserve neurologic function, slow disease progression, or improve survival even when direct clearance of the underlying agent is delayed, incomplete, or not feasible. Concepts that dene actionable windows for intervention, demonstrate benet in realistic late-stage models, and reveal convergent mechanisms across distinct neurotropic dis-eases are strongly encouraged. Technical focus areas:

• Identify reversible host-driven mechanisms of neurologic injury in late-stage disease;

o Focus on mechanisms that continue to drive CNS damage after symptoms begin.

• Discover biomarkers linked to disease progression, intervention opportunities, and pre-dictive outcomes;

o Test whether modulating host or host-pathogen processes can preserve neurologic function, slow progression, or improve survival even when pathogen clearance is in-complete

• Develop clinically relevant models, delivery methods, and outcome measures.

o Use realistic late-stage disease systems to evaluate novel CNS delivery of medical countermeasures and measure meaningful functional rescue and survival outcomes.

ARPA-H is particularly interested in research concepts that address discovery of critical meta-bolic and proteomic biomarkers linked to host-pathogen interactions, novel delivery methods of medical countermeasures (MCMs) - specically effective against late-stage neurotropic dis-eases - to the central nervous system, determination of clinically relevant treatment windows based upon molecular biomarker signatures, and measurable molecular features linked to clin-ically relevant outcomes are strongly encouraged.

Relevant references:

• https://www.pnas.org/doi/10.1073/pnas.1308817110

• https://www.mdpi.com/1999-4915/11/2/192

• https://journals.asm.org/doi/10.1128/jvi.01323-08

• https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2020.561530/full

• https://www.nature.com/articles/s42255-022-00652-3

• https://www.frontiersin.org/journals/immunology/arti-cles/10.3389/mmu.2025.1578202/full

Topic 6: Protecting Patient Data in Life Science AI

The rapid development and implementation of large language models (LLMs), biological de-sign tools (BDTs), and other foundation models in life sciences are driving ideation, discovery, and clinical care for industry and healthcare. At the same time these systems introduce new risks when trained on sensitive clinical, genomic, molecular, imaging, and/or longitudinal health data.

Recent publications have demonstrated that these models may unintentionally memorize and expose patient-linked information, enable discovery of specic patient’s data use for training, and/or remain vulnerable to prompt injection and other data extraction methods. While many of these vulnerabilities have been demonstrated on models in other elds, in life science models these concerns may be amplied because datasets often contain rare disease proles, unique genomic signatures, data from the same patient shared across models, familial-linked data, and multimodal patient records that are difficult to fully de-identify.

ARPA-H seeks proposals that dene and measure patient data privacy risks in life science AI while developing practical tools that help model developers reduce those risks without slowing innovation. These efforts should address challenges beyond simply screening, obfuscating, and/or removing known PII (Personal Identiable Information) in training data. Examples of po-tential research topics are below:

• Characterizing and defending against membership inference and model inversion in models trained on clinical, biological sequence, and structural data;

• Developing tools to measure data leakage and memorization in biological and patient-linked training datasets;

• Advancing scalable and provable machine unlearning methods so that sensitive rec-ords or data classes can be removed effectively from trained models;

• Creating automated evaluation pipelines and scorecards to baseline newly released models for privacy, robustness, and extraction risk;

• Securing agentic AI systems that connect models to biomedical design, clinical work-ows, or clinical environments;

• Methods uniquely suited for securing biological and clinical models from distillation attacks.

Research concepts which address multi-modal types of clinical and biological data – from imag-ing to genomics – are strongly encouraged.

https://www.pnas.org/doi/10.1073/pnas.1308817110 https://www.mdpi.com/1999-4915/11/2/192 https://journals.asm.org/doi/10.1128/jvi.01323-08 https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2020.561530/full https://www.nature.com/articles/s42255-022-00652-3 https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1578202/full https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1578202/full

ARPA-H is particularly interested in platforms that:

• Create common baselines for trusted model release, enabling developers, health sys-tems, and biotechnology organizations to compare privacy and extraction risk across models, modalities, and use cases.

• Support secure data reuse across the bioeconomy, allowing sensitive clinical, genomic, molecular, imaging, and longitudinal datasets to advance innovation while reducing the risk that patient-linked information is exposed.

Relevant references:

• https://www.nature.com/articles/s41586-026-10688-0

• https://pmc.ncbi.nlm.nih.gov/articles/PMC12680930/

• https://www.mdpi.com/1660-4601/20/15/6539

• https://dl.acm.org/doi/full/10.1145/3523273

• https://ieeexplore.ieee.org/document/9833649

• https://openreview.net/pdf?id=BpAx3OuNOr

• https://dl.acm.org/doi/abs/10.1145/3460120.3484756

Topic 7: Engineering DRT for Programmable DNA Synthesis as Emerging New Medical Countermeasures (MCM) Strategy

Recent discoveries in bacterial phage immunity pathways have identied defense-associated reverse transcriptases (DRTs) – which naturally confer protection against phages through cDNA synthesis – as the rst known biological system to challenge the last unbroken paradigm of the Central Dogma – protein to RNA to DNA. Two recent studies have shown that DRTs mediate protein-templated synthesis of sequence-specic concatemeric dinucleotide DNA. Notably, DRT3b was shown to synthesize a protein-primed poly(AC) strand in the absence of a nucleic acid template. These ndings, together with emerging structural data, create an opportunity to systematically interrogate microbial sequence databases for related systems and to drive mo-lecular engineering of DRTs for more precise and programmable DNA synthesis.

DRTs may also have substantial translational potential across multiple elements of health and disease. As components of bacterial immune defense, preliminary studies suggest possible an-tibiotic-free antimicrobial therapeutic applications, including direct induction of bacterial cell death and novel strategies to optimize phage libraries. In addition, the distinctive structural in-teractions between DRTs and their target proteins may enable new classes of detection plat-forms for protein-specic targets, including toxins and small-molecule pharmaceuticals. The fu-ture translational space for DRTs are well aligned with ARPA-Hs mission and may create a com-pletely novel line of therapeutics and diagnostics for human health. Examples of potential con-cepts include:

• Pursue bioengineering and synthetic biology approaches to reprogram DRT protein, enabling synthesized DNA motifs beyond current natural limitations;

https://www.nature.com/articles/s41586-026-10688-0 https://pmc.ncbi.nlm.nih.gov/articles/PMC12680930/ https://www.mdpi.com/1660-4601/20/15/6539 https://dl.acm.org/doi/full/10.1145/3523273 https://ieeexplore.ieee.org/document/9833649 https://openreview.net/pdf?id=BpAx3OuNOr https://dl.acm.org/doi/abs/10.1145/3460120.3484756

• Identify DRT regulatory mechanisms that can be leveraged for adaptive and precise read-write control of functional DNA products both intracellularly and in vitro;

• Explore DRT-linked apoptosis pathways to drive novel antimicrobial countermeasures strategy, especially against species resistant to traditional antibiotics;

• Investigate prokaryotic conservation of DRT protein-templated DNA synthesis para-digm and the breadth of conserved functions shared across prokaryotes for human-rel-evant biological control.

• Enable programmable novel therapeutic or countermeasure modalities by exploiting

DRT functions in microbial defense systems, including investigating their adaptability to mammalian systems and their potential to address urgent public health and national health security needs.

• Explore novel diagnostic, sensing, and other biochemical functions enabled by DRT protein-templated DNA synthesis that could accelerate therapeutic development.

• Generate foundational structural datasets and design rules for non-nucleic acid-tem-plated DNA synthesis to advance predictive structural modeling.

References:

• https://www.science.org/doi/10.1126/science.aed1656

• https://www.science.org/doi/10.1126/science.adq0876

• https://www.science.org/content/article/scientists-stunned-fundamentally-new-way-life-produces-dna

• https://www.frontiersin.org/journals/microbiology/arti-cles/10.3389/fmicb.2026.1866040/full

Topic 8: Prevention of Lethal Alpha-gal Allergic Responses Caused by Tick Bites

Alpha-gal syndrome (AGS) is an increasingly recognized severe allergic condition caused by tick bite-induced sensitization to galactose-alpha-1,3-galactose (alpha-gal). Subsequent expo-sures to alpha-gal found in consumed red meat, dairy, or certain medications can trigger de-layed, severe allergic responses making it challenging to immediately identify the source of ex-posure, resulting in missed diagnoses of AGS and increased risk of future exposures and life-threatening allergic reactions. Meanwhile, there are no clear diagnostic tools to predict AGS or interventions for patients with AGS beyond prevention of future tick exposures, strict avoidance of red meat, dairy, and select alpha-gal-containing medications. ARPA-H seeks to create com-prehensive immune mapping of tick exposure to elucidate the cellular and molecular pathways driving severe AGS.

ARPA-H seeks R&D approaches to identify and functionally map of tick-bite associated innate and adaptive immune responses that induce allergy, inflammation, and the transmission of tick-borne diseases. These efforts will leverage immune profiling to better understand tick-bite-in-duced host sensitization mechanisms and longitudinal disease trajectories.

https://www.science.org/doi/10.1126/science.aed1656 https://www.science.org/doi/10.1126/science.adq0876 https://www.science.org/content/article/scientists-stunned-fundamentally-new-way-life-produces-dna https://www.science.org/content/article/scientists-stunned-fundamentally-new-way-life-produces-dna https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2026.1866040/full https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2026.1866040/full

Examples of potential concepts include:

• Longitudinal cellular and serological immune profiling of alpha-gal exposed individu-als to support the discovery of novel clinical biomarkers of AGS and to develop AGS risk-scores for exposed patients.

• Comprehensive biochemical analyses, including glycolipid profiling of Lone Star tick saliva and bite transmission studies, to identify the molecular source and mechanisms of alpha-gal-induced allergy in humans.

• Comprehensive human allergy immune atlas following tick bite exposure to identify immune targets that could dampen or reduce allergic responses to alpha-gal.

• Develop deep multi-omic characterization of tick saliva allergens that drive anti-alpha gal IgE sensitization in asymptomatic and symptomatic AGS patients.

• Develop platforms to assess the dynamics of the innate and adaptive immune systems from tick saliva exposure and tick bite-associated disruption of epithelial integrity, and to define how these responses contribute to the development and severity of AGS.

• Develop a scalable immunological mapping and clinical biomarker platform to rap-idly identify recently exposed patients at highest risk of developing severe alpha-gal syndrome.

• Develop novel AGS treatment and prevention strategies to eliminate future tick bites and transmitted tickborne diseases.

Topic 9: SMILE (Smart Microbiome-Informed Lesion & Enamel restoration)

Dental caries (including tooth decay or cavities) are one of the most common chronic health conditions in the United States. More than 90% of adults and 46% of youth have untreated tooth decay, with disproportionate impact among the 1.7 million rural Americans living in “dental de-serts” without reliable access to dentists and the quarter of adults (72 million) who lack dental insurance. The health implications of tooth decay extend far beyond oral health, signicantly increasing risk of and worsening existing chronic conditions, such as heart disease, diabetes, respiratory inammation, and brain disorders. Treatment of dental caries relies on in-office pro-cedures to remove decayed tissue and subsequently protect healthy tissue with synthetic mate-rials such as composite resin, amalgam, or ceramic. While these materials are durable, llings typically need to be replaced every 5-10 years. Despite widespread adoption of oral hygiene practices that prevent dental caries, many patients experience recurrent caries despite good oral hygiene due to genetic factors associated with weaker enamel and oral microbiome imbal-ances that promote acid-producing bacteria. These challenges underscore the need for a fun-damentally new approach that is biologically informed, minimally invasive, durable, and acces-sible outside of clinical settings.

ARPA-H is interested in bold, interdisciplinary approaches that leverage recent advances in bio-inspired materials science and oral microbiome research to transform how dental caries are de-tected and treated. This topic seeks to develop microbiome-aware diagnostics and smart mate-rials capable of repairing early-stage tooth decay prior to the onset of irreversible tissue loss.

Proposers are encouraged to explore solutions that enable proactive, community-deliverable, or at-home interventions.

Proposed solutions may address one of two technical areas:

• Detect early-stage tooth decay and oral microbiome dysbiosis using low-cost, accessi-ble, and quantitative diagnostic approaches prior to the need for clinical intervention

• Repair enamel through bio-inspired materials that functionally restore tooth structure, integrate with native tissue, and demonstrate superior durability to current llings.

Concepts must dene strategies to demonstrate feasibility and rigor, and should include quan-titative metrics for performance (e.g., microbiome composition shifts, material durability, and biocompatibility) in appropriate early-stage model systems (biolms, cell culture models, organ-oids/organ-on-chip models, etc.) to enable in vivo validation.

Topic 10: Ending Preventable Deaths from Ectopic Pregnancy Through First-Visit Diagno-sis

Early pregnancy care urgently needs objective, point-of-care tools that allow clinicians to deter-mine pregnancy viability and location during the rst medical visit. Today, ectopic pregnancy remains difficult to diagnose, often requiring serial labs, repeat imaging, emergency visits, or referral to clinicians with advanced ultrasound expertise. Ectopic pregnancies cannot result in a viable birth and missed or delayed diagnosis can lead to rupture, hemorrhage, infertility, and preventable maternal death. Due to the emergent nature of this condition, a missed diagnosis can have disproportionate impact in rural and settings with limited access to timely advanced care.

ARPA-H seeks revolutionary technologies that can effectively resolve the diagnostic uncertainty of pregnancies of unknown location by enabling same-day differentiation of viable intrauterine pregnancy, early pregnancy loss, and ectopic pregnancy.

Proposers are encouraged to focus on one of the following areas and propose both technology development and clinical adoption approaches:

• Point-of-care tools to distinguish viable intrauterine pregnancy, failing intrauterine pregnancy, and ectopic pregnancy.

• Biomarker or multi-analyte tests to assess early pregnancy viability.

• Targeted ultrasound contrast or imaging approaches to localize nonviable pregnan-cies.

• Ectopic pregnancy classification and risk models to predict hemorrhage or placenta accreta spectrum.

Technologies should demonstrate improved performance over current standard of care for identifying early pregnancy location and support same-day treatment planning. Solutions must be highly innovative, clinically relevant, scientically plausible, and designed for real-world adoption, including coverage by insurance and Medicaid. Proposers should articulate a credible pathway to clinical integration, cost reduction, and use in settings where subspecialty imaging expertise is limited. ARPA-H seeks bold, rst-of-kind approaches rather than incremental im-provements to existing workows. Additionally, ARPA-H encourages submissions of collabora-tions between MDs and PhDs.

Topic 11: Transforming the Well-Woman Exam through Objective Data

The well-woman exam is a trusted institution, but there is almost no objective reproductive-health data to guide the interaction between the provider and the patient. In routine care, clini-cians often rely on history, physical exam, and patient-reported symptoms to detect high-burden reproductive conditions such as endometriosis, Polyendocrine Metabolic Ovarian Syndrome (PMOS), broids, infertility, and menopause timing. As a result, many patients experience de-layed diagnosis, delayed intervention, or are left to seek answers through direct-to-consumer products, particularly in areas with limited OB/GYN provider access.

While tests to detect specic diseases are emerging, they will likely be accompanied by prior authorization requirements and questions around who should be tested. An overall test of re-productive health would help determine who is referred for specialists and tested for specic reproductive disorders.

ARPA-H seeks proposals to address the lack of objective reproductive health data in routine care, which limits the value of the well-woman exam and constrains early detection of high-burden conditions. This may include novel objective screening technologies that can be used at home, in primary care, or in routine gynecologic care to identify patients who need additional evaluation for an underlying reproductive condition. This should not be focused on one specic disease, but overall reproductive health.

Proposers are encouraged to focus on solutions meeting the following guidelines:

• Screening for women with reproductive conditions such as endometriosis, PMOS, -broids, diminished ovarian reserve, primary ovarian insufficiency, and perimeno-pause/menopause onset.

• Tests should aim to identify patients who warrant further evaluation by a specialist, not to provide a denitive diagnosis.

• Solutions may include point of care diagnostics, physiologic monitoring, imaging, and other reproductive organ health assessment tools.

• AI and computational techniques may be part of the solution, but solutions proposing such models as a standalone solution are discouraged.

• Technologies should focus on actionable screening and risk stratication rather than incremental improvements to exam-room devices.

Solutions should demonstrate clinically meaningful sensitivity against current standards of care, without requiring specialist referral as the rst step. Successful technologies will enable earlier, more accurate detection of reproductive disorders and reproductive lifespan transitions such as perimenopause/menopause, expand the scope of the well-woman exam, and create scala-ble platforms that modernize women’s health care. Proposed approaches must be scientically plausible, clinically actionable, highly innovative, and designed for coverage by insurance, including Medicaid. Additionally, ARPA-H encourages submissions of collaborations between MDs and PhDs.

Ideally, this solution will allow most women to be cared for by a family medicine provider, only being referred to an OBGYN when needed.

Topic 12: Innovations in Biotransport to Support Long-Term Preservation of Tissues and Organs

While cryopreservation advances are enabling long-term cryopreservation of increasingly larger biological form factors, preservation of whole transplantable organs is still extremely hard due to multiple technical hurdles, including cryoprotective agent (CPA) toxicity and difficulty deliv-ering CPAs uniformly throughout tissues. For example, to prevent the formation of ice through-out the entire organ, CPAs must reach all regions at effective concentrations. Fundamental bio-transport limitations, particularly restricted and nonuniform penetration of protective agents into thick, heterogeneous tissues, remain a critical barrier to achieving intracellular delivery of pro-tective molecules at scale. These limitations prevent robust, long-term preservation and bi-obanking of tissues and organs at any temperature, constraining the availability, logistics, and equitable delivery of these advanced regenerative therapies. Success on this front would dra-matically expand tissue and organ supply, transform transplant logistics, and broaden equitable access to tissue and organ based therapies by making long-term preservation of transplantable organs a near-term possibility.

ARPA-H seeks bold, cross-disciplinary solutions to overcome the fundamental transport limita-tions that currently prevent reliable preservation of thick tissues and whole organs. We are par-ticularly interested in approaches that enable highly efficient, low-toxicity distribution and re-moval of protective agents throughout complex microvascular networks. Concepts that rethink organ geometry, leverage advanced materials or nanotechnology, or integrate predictive mod-eling with real-time feedback and automation are especially encouraged.

Proposed concepts may encompass innovations in techniques, platforms, and/or integrated technologies that:

• Achieve rapid, uniform distribution and intracellular uptake of protective molecules throughout engineered or donated tissues and intact organs with diverse geometries, dimensions, and vascular architectures;

• Quantitatively characterize and control transport using measurable, system-level pa-rameters (e.g., effective permeability, penetration depth, saturation kinetics, spatial uni-formity indices); and

Establish design rules and tunable parameters that can be tailored to specic tissue and organ types (e.g., heart, kidney, liver, composite tissues).

Concepts should be supported by clear experimental or computational strategies to demonstrate feasibility and rigor, such as:

• Model systems spanning relevant length scales (e.g., mm-scale tissue slabs to whole organs),

• Quantitative imaging or biosensing to map intratissue distribution and intracellular lo-calization,

• Predictive modeling of transport

Robust metrics for technical performance (e.g., post-treatment viability, function, mechanical in-tegrity, and biomarker proles), impact, operability, and commercialization potential are ex-pected.

Topic 13: Organs-in-Action: Next-Generation Human Tissue Platforms for Longevity, Dis-ease, and Therapy Discovery

Nonclinical research has rapidly embraced New Approach Methodologies (NAMs), including organoids, organ-on-chip platforms, and advanced in silico tools, to improve human translation and reduce reliance on animal models. While these innovations represent important progress, ARPA-H is interested in tackling an even greater challenge: creating transformative, human tis-sue-based disease models that operate at true tissue and organ scales. ARPA-H seeks next gen-eration human platforms that leap beyond organoids and lab-on-chips in order to capture multi-cellular tissue-level organization, patient-relevant complexity (e.g., immune, stromal, neural, vas-cular components) and dynamic biochemical processes specically for studying longevity in vivo, which may include modeling capabilities for aging, disease progression, and treatment response at organ and system scales. The overarching goal is to reshape how we discover, test, and personalize interventions for longevity and across a wide range of diseases by closing the gap between traditional preclinical systems and actual human pathophysiology. Approaches must include technical, impact, operational and commercialization metrics.

Examples of potential concepts include:

• Longitudinal “time lapse” models that utilize human tissues (e.g., ovaries, uterus, heart, kidney, bone marrow) and are equipped with controllable “aging drivers” that acceler-ate key aging processes in vitro.

• Multi-organ human metabolic disease circuit by interconnecting a set of human tissue modules, such as liver, pancreas, adipose tissue, skeletal muscle, and gut epithelium with a shared microuidic circulation to model systemic changes and recapitulate key hallmarks of metabolic disease.

• Next-generation human lung injury and infection platform using human lung alveolar-capillary model that includes key epithelial, endothelial, stromal, immune, and surfac-tant components under realistic breathing or ventilation conditions.

• Vascularized, innervated human musculoskeletal unit for chronic pain and degenera-tion by combining muscle, tendon, bone, and cartilage with integrated blood vessels and sensory/motor neurons to engineer a system that can be subjected to controlled mechanical loading and inammatory or injury signals, with readouts of electrophysiol-ogy, contractile function, and pain signaling.

• Directly connect with new approach clinical trials using NAMs with high potential for regulatory clearance;

• Integrate emerging organ-scale or high-throughput organoid/organ-on-chip technolo-gies, native and/or engineered tissues, synthetic biology, and rich in situ data streams;

• Support high-throughput perturbation and longitudinal molecular, functional, and structural measurements; and

• Undergo rigorous validation against human clinical and real-world data

Topic 14: Near real-time, Non-contact Determination of Sterility in Distributed Manufac-turing Systems

Distributed manufacturing systems shrink manufacturing footprints from large warehouse sized buildings making tens of thousands of units at once, to small often portable systems making tens of units at once. One of the major use cases for distributed manufacturing is to shorten supply chains, bringing products closer to the users, and creating an on-demand production capacity. However, many of the quality control steps used at large manufacturing sites for huge volumes of product do not translate directly into small automated systems that are producing small batches. Most distributed systems require miniaturized, automated, and real time sensors to fulll the quality assurance and testing functions that a team of quality engineers and systems would normally perform. Sterility assessments are typically reliant on colony growth metrics ap-plied to lter membranes or directly through inoculation. Other methods that determine bio-burden still typically require direct access to the substance being tested and often cannot meas-ure a sterility assurance level (SAL) of 10-6.

ARPA-H seeks truly innovative, cross-disciplinary solutions that can overcome the time limita-tions of current tests which take between three (3) and 14 days, as well as batch size limitations.

When a batch is less than 10 units, destructively testing a unit for sterility is functionally imprac-tical. Detection of organic molecules is not sufficient for sterility determinations due to the need to test for the viability of any microorganisms. ARPA-H is particularly interested in non-contact evaluation technologies that can measure the presence and amount of metabolic activity within a clear container lled with sterile solutions of small molecule or biologic prescription drugs.

Concepts that rethink the measurement of biologic activity, leverage novel spectroscopy tech-niques, advanced or active materials, and integrate predictive modeling techniques are espe-cially encouraged.

Proposed concepts may use any technology platform or technique that:

• Rapidly evaluate variable volumes (2milliliters – 1 liter) of sterile pharmaceuticals in their original containers without compromising the sterility of the sample

• Quantitatively measure metabolic activity in samples down to a SAL of 10-6

• Create sampling models for common sample form factors

• Reduce the space and time required to perform sterility testing so that it could be feasi-bly done in-line with distributed manufacturing systems

Concepts should be supported…