Citrate-functionalized manganese oxide nanoparticles in neonates ≥35 weeks gestation at risk of acute bilirubin encephalopathy: a phase 1 observational trial

Acute bilirubin encephalopathy (ABE), regardless of cause, when not monitored or treated aggressively is usually irreversible and likely to result in lifelong neurological disability and kernicteric mortality.^1,2,3,4,5 Resource-constrained communities continue to endure a disparate burden, even as adverse events are being minimized through world-wide implementation of international guidelines to prevent severe neonatal hyperbilirubinemia (SHB).^5,6 Although in India, these improvements are being accelerated by access to affordable phototherapy,⁷ timely healthcare access continues to challenge our clinicians. Frequently, practicing clinicians encounter newborns with progressive SHB who are rushed from home, often at dire risk of impending death.^8,9 Inability to timely intervene with an ExTx, mostly attributed to the lack of cross-matched blood or delays in bedside access, results in significant neonatal mortalities.^10,11,12

In view of these national and global challenges, there is a critical need for therapeutic interventions capable of rapid bilirubin degradation stabilizing the rate of rise to prevent SHB associated neurotoxicity. Our earlier preclinical studies demonstrated the safety and efficacy of a single dose of citrate-functionalized tri-manganese tetrahydrate nanoparticles (C-Mn₃O₄ NPs) in reversing SHB.¹³ This nanoparticle (i.e., the nanodrug) interacts directly with bilirubin, degrading it to methyl vinyl maleimide, a known phototherapy byproduct that is enterally eliminated.¹⁴ In SHB rodent models (with induced hemolysis), single oral dose of the nanodrug significantly reduced both total serum bilirubin (TSB) and unconjugated bilirubin (UCB) within 4 - 8 h.¹³ Neural bilirubin load was reduced by ~85% along with improvements in neurobehavioral indices, neuromotor movements, and cognitive functions (learning and memory). Further histological analysis revealed that the nanodrug prevented characteristics SHB-induced neural cell destructions in Purkinje and substantia nigra regions, as well as eosinophilic degeneration, spongiosis, and cell shrinkage within brain parenchyma. Rodent safety data from our laboratory confirmed absence of known drug toxicity at the intended single dose and even after repeated administration over 90 days.^15,16

Building upon the robust preclinical evidence, the principal investigator (AKM) initiated the Institutional Ethics Committee (IEC)-approved prescriptive-use administration of the experimental nanodrug in neonates with SHB at risk for ABE after extensive personal and peer deliberation and formal institutional ethics committee approval. This decision reflected an ethical response to imminent risks of death or irreversible brain injury in a cohort, where traditional interventions were insufficient, and a pilot clinical path offered potential therapeutic benefits. The primary objective of this limited prescriptive protocol was to evaluate whether a single oral dose of C-Mn₃O₄ NPs could decrease SHB related mortality. Secondary objectives include reduction in the need for ExTx and decrease in the duration of adjunctive phototherapy. It is with trepidation, but in the spirit of scientific transparency, we present this analysis, to share the lessons learned from this pilot application and to provide foundational data for any future clinical studies envisaged by our national regulatory agencies.

Ethical approach

In compliance with institutional processes, we initiated a three-step project proposal that would eventually lead to a single-center, placebo-controlled, randomized controlled trial of this experimental nanodrug. We initiated a request to the Indian Council of Medical Research (ICMR, New Delhi) to sponsor our clinical research proposal seeking a multi-center investigation. Concurrently, anticipating a lengthy process, we also sought institutional approval for a limited pilot use of the experimental nanodrug under strict inclusion criteria. The study was approved by the Institutional Ethics Committee (NRSMC/IEC/96/2022; NRSMC/IEC/18/2024) after notifying the Central Drugs Standard Control Organization and was registered with the Clinical Trials Registry – India (CTRI/2023/02/049596; CTRI/2024/07/071406). Upon approval, we embarked on what we perceived was a humanitarian effort. We were cognizant of the risk to our scientific integrity and adherence to “first, do no harm” principle. In the meantime, we continued to seek commercial pharmaceutical partnership that would innovate our drug development for eventual clinical prescription. A few months ago, the ICMR temporarily paused our “experimental” activities to conduct an independent extensive pending review of our experimental protocols to validate our rodent laboratory data. This process is now complete and a nationwide multicentric trial is in the process of approval. Upon compliance with the ICMR regulatory guidance, we realized that we had generated an unplanned comparative dataset. The lead authors (AKM and AA) requested their former laboratory study mentor (VKB), who had no prior clinical knowledge or participation in the prescriptive use of this nanodrug, to independently review the study and invited him to co-author this joint report.

Study subjects

Neonates admitted to the Level III neonatal intensive care unit (NICU) at NRS Medical College and Hospital (NRSMCH) for SHB receive intensive phototherapy and serial TSB monitoring per AAP guidelines.^17,18 The study population specifically targeted neonates requiring escalated phototherapy¹⁷ and/or those nearing the TSB thresholds for ExTx.¹⁸ Parents or legal guardians of eligible neonates (see ‘Inclusion and Exclusion Criteria’ section) were additionally offered to enroll their newborn to a pilot study protocol for the adjunctive use of the experimental nanodrug. Parental informed consent, in accordance with local regulations, was obtained for each subject by non-clinical personnel. Enrolled subjects were screened and assigned to the prescriptive oral dose, and their clinical course was prospectively observed and documented (Phase IA & IB). Their outcomes were compared against a subsequent quasi-control cohort managed exclusively under standard AAP guideline without the experimental nanodrug (Phase II). This structural transition occurred after the ICMR mandated a temporary suspension of the nanodrug administration for interim analysis. Subjects with both hemolytic and non-hemolytic SHB were included in the study. The entire cohort, reviewed for newborn SHB management, was chronologically categorized as Phase IA: SHB managed by AAP guidelines¹⁷ and adjunctive use of the experimental nanodrug; Phase IB: clinically managed using the more recent 2022 AAP guidelines¹⁸ as well as the experimental nanodrug; Phase II: managed solely by 2022 AAP guidelines¹⁸ without the experimental nanodrug.

Inclusion criteria

1. (i)

   Infants (inborn or outborn) with TSB above the 95th percentile on the Bhutani nomogram (phase IA) and requiring phototherapy or, at risk of requiring escalated phototherapy per AAP 2022 guidelines (gestational age ≥ 35 weeks) (phases IB and II).

2. (ii)

   Rate of TSB increase ≥ 0.2 mg dL⁻¹ per hour.

3. (iii)

   Infants with any signs of ABE (i.e., BIND Score ≥ 1).

Exclusion criteria

1. (i)

   Absence of informed consent from a legally acceptable guardian.

2. (ii)

   Presence of moribund congenital anomalies.

3. (iii)

   Congenital gastrointestinal conditions requiring surgery.

4. (iv)

   Cholestasis with direct bilirubin > 1 mg dL⁻¹.

Bilirubin reduction interventions

Phototherapy prescription

Intensive blue-light phototherapy (irradiance range 460–490 nm), with an irradiance of 30–35 µW cm⁻² nm⁻¹ using institutionally acquired device (Nice Neotech Medical Systems, India), and average body surface area exposed (65–80%).^19,20

Exchange transfusion

Double volume, ExTx was performed using cross matched fresh, CMV-negative, irradiated blood constituted with PRBC and plasma to yield a hematocrit of 45%. Intervention was planned when newborn’s hour specific TSB reached the designated AAP-defined thresholds. Other indications included (i) onset of any clinical sign suggestive of ABE guided by the BIND score²¹; (ii) TSB rate-of-rise >2 mg dL⁻¹ after 6 h of phototherapy or persistence above phototherapy thresholds. Requests to the blood bank were followed by standard Indian practice.¹²

Experimental nanodrug prescription

Neonates assigned to Phase IA and IB, were adjunctively administered a single oral dose of 0.05 mL of the experimental nanodrug (i.e., C-Mn₃O₄ NPs), by the attending neonatologist. The intervention was not blinded. The decision to initiate the nanotherapeutic was independent of the specific duration or the number of phototherapy sessions already received. There was no restriction on feeding status, and no repeat dose was administered in case of emesis. All clinical care was at the discretion of the attending neonatologist and delivered by their team of fellows, residents, and NICU staff, and the clinical variables were recorded by the research team.

Drug preparation and dosage

The experimental nanodrug was synthesized at a good manufacturing practice (GMP) certified pharmaceutical manufacturing facility (Akshar Molecules Inc, Haryana, India) in strict accordance with the regulatory standards of the Government of India.

A standardized, fixed dose was administered throughout the study. This dosage was extrapolated from in vivo animal efficacy data and calculated for a baseline average neonatal weight of 3.0 kg in West Bengal, India. Given the “proof-of-concept” nature of this study and the restricted ethical scope associated with experimental neonatal therapeutics, a dose-escalation or multi-regimen study was not pursued.

Outcome measures

Our primary outcome measure was the reduction in neonatal mortality. Secondary outcome measures included the need for ExTx and the duration of phototherapy, incidence of adverse events and post-discharge clinical outcome. Safety profiles also included monitoring for any side effects including skin rash or photosensitivity, emesis or diarrhea, joint swelling, temperature instability and edema. Comprehensive long-term neuro-developmental follow-up was planned but not reported here.

TSB screening and other clinical measurements

Subjects were monitored for clinical status and vital parameters by trained NICU staff. Demographics and all clinical parameters were prospectively documented on pre-specified case record forms. TSB was measured at baseline: pre-intervention (Phase I) or at admission to NICU (Phase II) (Zero), and post-intervention (2, 6, 12, 24 h) until discharge/death. Samples were handled under strict cold-chain, light-shielded conditions and analyzed using a diazo-based method (LIQUIXX Bilirubin (total & direct) estimation kit, Erba Mannheim, Germany) on the Cobas Integra 400 Plus autoanalyzer (Roche Diagnostics, Switzerland) at the NRSMCH Central Laboratory following standards mandated by the National Accreditation Board for Testing and Calibration Laboratories (NABL).

Key safety and efficacy assessments included Kramer’s jaundice staging and the BIND score,²¹ supplemented by other assays (CBC, G6PD enzyme, direct Coomb’s test, electrolytes, etc.) as clinically indicated. Neurological and developmental evaluations including brainstem evoked response audiometry (BERA) and the Hammersmith Infant Neurological Examination (HINE),^22,23 were conducted at discharge, and at follow-up visits on days 8, 30, 90, and 180 respectively to monitor safety and detect bilirubin-related neurotoxicity.

Follow up

Comprehensive outpatient clinical and neurological examination and developmental assessment were scheduled at 3, 6, and 12 months, at parents’ convenience and accessibility (planned and recommended).

Statistical analysis

Continuous data were first assessed for normality and homogeneity of variance; variables meeting these assumptions were analyzed using an unpaired two-tailed Student’s t-test, while the Mann–Whitney U test was used for all others. Categorical variables were analyzed with Fisher’s exact test. For the primary outcome (death or ExTx), treatment efficacy was quantified by calculating the Odds Ratio (OR), Relative Risk (RR), Absolute Risk Reduction (ARR), and Number Needed to Treat (NNT) from a standard 2 × 2 contingency table, with significance assessed by the Chi-squared (χ²) test. Observational risk factors for ABE were explored using logistic regression (OR, 95% CI). To evaluate post-ExTx TSB trajectories, we employed linear mixed effects modeling tailored for unbalanced longitudinal data, explicitly addressing heterogeneity in timepoint availability, missingness patterns, and subject-specific variation. Differences in the duration of phototherapy were estimated via Kaplan-Meier analysis and reported as Hazard Ratio (HR) and 95% CI. Statistical significance was set at a two-sided P ≤ 0.05. Statistical analysis was performed using GraphPad Prism v9.0 (GraphPad Software Inc., MA) or MATLAB vR2024b (MathWorks, MA).

Serious adverse events

All reported adverse events were systematically assessed independently. Moderate and serious events were defined according to established neonatal care protocols for phototherapy and ExTx, with additional evaluation for possible association with the investigational experimental nanodrug. Serious adverse events were classified as those resulting in death, life-threatening events, persistent or significant disability/incapacity, prolonged hospitalization, or clinically significant skin reactions.

Between November 2022 and July 2025, 216 neonates met the screening criteria for escalated hyperbilirubinemia care, of whom 207 were enrolled after exclusions for protocol ineligibility (n = 4), parental refusal (n = 3) and logistical constraints (n = 1) (Supplementary Fig. S1). All enrolled neonates were less than one week of age. The median age at admission was 83.0 h (range: 10–225 h) and the median pre-treatment TSB was 26.6 mg dL⁻¹ (95% CI: 25.2–27.5 mg dL⁻¹). One hundred twenty neonates (57.9%) were male; 41 (19.8%) had G6PD enzyme deficiency; 79 (38.2%) had ABO or Rh isoimmunization; and 84 (40.6%) had a gestational age <38 weeks (Table 1). Clinical risk factors for degree of prematurity, ABO/Rh isoimmunization, and postnatal age (<60 h) were not significantly associated with ABE (Table 2). By contrast, G6PD enzyme deficiency conferred 3.8-fold higher odds of ABE (OR = 3.8, 95% CI: 1.8–8.1; p = 0.0006), identifying it as the single strongest baseline predictor.

Experimental nanodrug plus phototherapy was used in 170/207 neonates categorized in Phase IA (n = 124) and Phase IB (n = 46). The remaining 37 patients constituted Phase II, serving as a quasi-control group. These participants were managed exclusively with standard-of-care phototherapy after the ICMR mandated a temporary suspension of nanodrug administration to conduct an interim analysis of the study protocol and preliminary safety data. During this hiatus, clinical and biochemical parameters of SHB were prospectively monitored to provide a comparative baseline against the intervention cohorts. In phase I, two deaths (1.2%) occurred, both attributable to congenital cardiac defects and unrelated to bilirubin or drug toxicity. In contrast, those treated with phototherapy alone (Phase II; n = 37/207), six deaths (16.2%) occurred, all secondary to bilirubin encephalopathy. Four of the six deaths occurred even before an ExTx could be performed. Notably, mortality was observed exclusively in neonates with clinical signs of ABE at admission. The onset of ABE was noted less frequently in Phase IB (3/46) as compared to Phase II (26/37). In the combined Phase IA & IB cohort, the experimental nanodrug significantly reduced the neonatal mortality (OR = 0.06, 95% CI:0.01–0.26), corresponding to 94% reduction (Fig. 1a) compared to the untreated neonates (Phase II). Relative Risk (RR) of neonatal mortality was 0.07 (95% CI:0.02–0.31), with an Absolute Risk Reduction (ARR) of 15.0% (95% CI:2.1–28.0%) and a “Number Needed to Treat” (NNT) of 7 (95% CI:3–20).

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a Neonatal mortality. The experimental nanodrug treated cohort comprises infants from Phase IA (n = 124) [managed with 2004 AAP guidelines] and Phase IB (n = 46) [managed with 2022 AAP guidelines]. Deaths (n = 2) in Phases IA were attributable to congenital cardiac anomalies and unrelated to bilirubin toxicity. No deaths occurred in Phase IB. Cohort that was not exposed to the experimental agent, “quasi-control” (phase II, n = 37), experienced six deaths, all secondary to bilirubin encephalopathy. b ExTx frequency. Statistical comparison was restricted to Phase IB and Phase II cohorts with identical inclusion criteria and the AAP 2022 treatment guidelines. In the no nanodrug group (Phase II), four out of six infants died before ExTx could be performed. Of the 33 remaining infants, one required a second ExTx. For our calculations, each infant was counted only once.

In the overall cohort (Phase I and II), 55/207 neonates met ExTx indication; however, only 50 underwent the procedure because blood could not be arranged for the rest (Supplementary Table S1). Initiation of ExTx, based on signs of ABE or the requisite hour-specific TSB thresholds differed markedly between the experimental nanodrug treated and untreated neonates (Fig. 1b). Among treated neonates, 13.7% (17/124) in Phase IA and 26.1% (12/46) in Phase IB (combined = 17.1%; 29/170) required ExTx, compared with 81.1% (30/37) in Phase II. In Fig. 1b, we restricted the analysis to a direct statistical comparison of ExTx use between Phase IB vs Phase II, both cohorts managed similarly in accordance with recent AAP guidelines (18). The reduced reliance on ExTx was reported by OR = 0.08 (95% CI: 0.03–0.23; p < 0.0001; χ²(1) = 24.8) with RR = 0.32 (95% CI: 0.19–0.52), and ARR of 54.9% (95% CI: 32.3–70.4%). The NNT was 2 (95% CI: 2–3) corresponding to a 68% relative reduction in the need for ExTx (p < 0.0001). One neonate from Phase II cohort required additional ExTx within 24 h.

Duration of phototherapy exposure was significantly reduced (P < 0.001) for experimental nanodrug-treated neonates both with and without ABE; mean duration = 18.0 ± 9.8 h (n = 46) versus 57.4 ± 20.7 h (n = 37) with mean difference of –39.4 h (95% CI: −45.2 to −33.6; p < 0.0001) (Supplementary Fig. S2). Kaplan–Meier analysis (Fig. 2) demonstrated a highly significant difference in the time to phototherapy cessation between cohorts (i.e., IB vs II). The Hazard Ratio (HR) of 12.9 (95% CI:6.8–24.4; log-rank p < 0.0001) indicated that treated neonates were approximately 13-fold more likely to cease phototherapy at any given time point than untreated neonates. Specifically, among neonates with ABE, mean duration of phototherapy was 22.5 ± 13.1 h in the experimental nanodrug treated cohort versus 56.7 ± 22.4 h (p < 0.0001) of the untreated. On the other hand, mean phototherapy exposure among neonates without ABE was 16.7 ± 8.5 h versus 58.9 ± 17.8 h (p < 0.0001) (Supplementary Fig. S2).

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Statistical comparison was restricted to Phase IB (nanodrug-treated, n = 46) and Phase II (no nanodrug treatment, n = 37) cohorts with identical inclusion criteria. a Kaplan–Meir curve showing the probability of phototherapy cessation with time. b Number of infants undergoing phototherapy during 0–96 h after initiation of drug treatment. Time “0” indicates initiation of phototherapy. The number in parenthesis indicates neonates demised during the period and censored from the analysis.

Rate of TSB reduction was similar for neonates during, immediate, and consequent 22 h of ExTx regardless of nanodrug intervention. Thus, stabilized post-transfusion bilirubin levels were observed (Fig. 3a, b). After 22 h post-ExTx, untreated neonates exhibited a modest but significant TSB rebound (p < 0.05). Rebound hyperbilirubinemia (post ExTx TSB increase > 0.2 mg dL⁻¹ h⁻¹) occurred in 24.1% (7/29) of treated neonates versus 40.0% (10/25) of controls (Fig. 3c).

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a The TSB level before and after ExTx. The nanodrug did not interfere with ExTx performance. At 22 h post-ExTx, untreated infants exhibited a modest but significant TSB rebound (p < 0.05). b TSB decay rate as analyzed using a linear mixed effects modeling tailored for unbalanced longitudinal data, explicitly addressing heterogeneity in timepoint availability, missingness patterns, and subject-specific variation. The bold line within each box plot indicates the median decay rate. The box represents the interquartile range (25th–75th percentiles), and the whiskers show the full range (minimum to maximum). c Post-ExTx an increase in TSB level (TSB increase >0.2 mg dL^−1 −1) was observed in 24.1% (7/29) of treated infants versus 40.0% (10/25) of controls.

Adverse events recorded during the study are summarized in Table 3. No instances of anaphylaxis, septic shock, or experimental nanodrug-related death were observed. Two disease-related deaths were reported in the combined Phase I cohorts; both were attributed to congenital heart disease. Among the Phase II cohort, there were six bilirubin-related deaths (23.1% of ABE cases). The only other reported key event was temperature instability (n = 2 in the treated cohort versus n = 4 in the untreated cohort). No other serious or minor adverse events were noted. However, in 145/168 survivors (86.3%) of the Phase I cohort who completed 6‑month clinical follow‑up demonstrated delayed milestones (n = 5/145; 3.4%), mild hearing loss (n = 2/145; 1.4%), and mild retino‑optic pathway dysfunction (n = 1/145; 0.7%). These data compared to Phase II cohort (27 of the 31 survivors (87.1%)): 13/27 (48.1%) showed delayed milestones (two with HINE scores <53), mild hearing loss (n = 8; 29.6%), severe hearing loss (n = 2; 7.4%), and 1 (3.7%) was identified with occult intrasacral meningocele.

Neither prematurity, sex, birth weight, G6PD status, nor isoimmunization significantly modified efficacy of the experimental nanodrug therapy in multivariate analysis (Supplementary Table S2). A trend toward shorter phototherapy exposure was observed among more mature neonates (p = 0.053).

Our prescriptive use of the experimental nanodrug as an adjunct to escalated phototherapy was limited to neonates deemed at highest risk for imminent and early signs of ABE. Administration of the nanodrug was associated with a marked reduction in neonatal mortality, approximately 94% lower than in the untreated cohort. Notably, all the observed deaths occurred in babies admitted with ABE. This subgroup of neonates (receiving adjunctive nanodrug) presenting early ABE during their first week of life, kernicteric deaths were virtually eliminated. In contrast, neonates not receiving the nanodrug experienced a 23.1% (6 of 26) mortality rate secondary to ABE. The nanodrug also significantly reduced the need for ExTx. Among neonates meeting identical inclusion criteria based on the 2022 AAP guidelines, only 26.1% of the nanodrug-treated infants required ExTx compared with 81.1% in the untreated group, who continued to exhibit total serum bilirubin (TSB) levels above the recommended treatment threshold. Phototherapy duration was notably shorter in the  nanodrug-treated group (median 12–24 h) compared with the untreated group (median 50–60 h). No experimental nanodrug-related serious adverse events, acute toxicities, or delayed mortality were reported. Bilirubin load reduction was substantial in the treated cohort, post-ExTx rebound hyperbilirubinemia was significantly higher in the untreated cohort (including one requiring repeat ExTx).

Lessons that we learned allow us to explore plausible basis for our observations. Preclinical and mechanistic data demonstrated the experimental nanodrug’s capacity to degrade bilirubin, accelerate bilirubin clearance, and reduce the cumulative neurotoxic exposure to the rodent central nervous system that appear feasible in human neonates. This chemo-preventive approach to reduce hyperbilirubinemia is similar to prescription of bilirubin oxidase feedings to delay ExTx in a term neonate²⁴ as well as its trial of 22 days of bilirubin oxidase feeding in 4 children with Crigler Najjar syndrome.²⁵ Clinically, we anticipated and observed with our nanodrug: (a) lowered proportion of infants whose TSB trajectory crossed conventional ExTx thresholds despite phototherapy, (b) blunting of the anticipated post-exchange rebound hyperbilirubinemia, and (c) shortening of phototherapy exposure. Notably, there was reduction in progression to ABE and its lethal consequences. The therapeutic effect appeared independent of common baseline covariates: gestational age, sex, isoimmunization, and age at admission. However, G6PD deficiency, previously recognized as a determinant of both hemolysis and vulnerability to neurotoxicity, was the strongest baseline predictor of ABE among neonates with SHB. The experimental nanodrug appeared to be protective against overt bilirubin neurotoxicity in the G6PD deficient cohort, a topic for future investigation for both individual and public health considerations.

We have only reported preliminary findings of 6th month clinical follow-up because kernicterus spectrum disorders necessitate a comprehensive neurological follow-up through neurodevelopmental assessments. A separate comprehensive neurological report after 3–5 years follow‑up is planned. Even though, safety findings in this cohort seemed reassuring but could be viewed biased. Therefore, a blinded, randomized controlled trial (RCT) has been designed for next. Furthermore, we remain concerned that manganese, though an essential trace element, is theoretically neurotoxic after chronic exposure. To ensure a safety profile, the drug formulation attempted to improve biodistribution by incorporating citrate to functionalize the experimental manganese oxide nanoparticles. This process is known to enhance the drug’s aqueous stability to facilitate rapid clearance and minimize bioaccumulation in neural tissue. This intended effect was validated in preclinical rodent data.^13,14,15,16 Nevertheless, because both short-term and long-term neurodevelopmental toxicities could be delayed or subtle, prolonged post-discharge surveillance remains essential.

While our study provides preliminary evidence for the adjunctive use of the experimental nanodrug to reduce kernicteric mortality, we note several limitations. Firstly, this report is not of a placebo-controlled RCT but a comparative study of chronological, quasi-control cohorts (Phase I vs Phase II), which could be vulnerable to selection or temporal bias. Secondly, the smaller control group (n = 37; Phase II) relative to the intervention cohorts (Phase I) limits the statistical power of the data. Lastly, our study is that experienced in a resource-constrained publicly funded teaching hospital NICU in West Bengal, India, which is known for its high baseline mortality rates. Thus, this experience should not be generalizable to high-income countries with mature health care systems with far better neonatal outcomes.

Ethical concerns arising from this 31-month saga merit explicit discussion. Structural barriers, unrelated to knowledge deficit, frequently impeded timely access to essential, preventive, and urgent life-saving interventions. These challenges underscore the inherent tension between addressing urgent clinical need and maintaining national regulatory compliance. Such dilemmas are not unique to this study and have been documented within the Indian clinical research landscape.^26,27 For NICUs in India, adherence to ICMR and institutional guidelines is imperative. Based on our unplanned yet informative observations, we propose a prioritized approach to conduct regulatory-compliant investigations that bridge laboratory observations and clinical validation.

In conclusion, we learned, the beneficial observations from our pilot, adjunctive C-Mn₃O₄ nanoparticles, augmented phototherapy efficacy. Now, we are motivated to urgently conduct rigorous confirmatory clinical trials in accordance with regulatory compliance. These preliminary observations offer an insight into this experimental nanodrug’s capacity to substantially reduce neonatal mortality, shorten phototherapy duration, and decrease ExTx reliance among neonates with SHB. Neonates with progressive SHB, especially those with G6PD deficiency or at risk for ABE, can be offered hope in resource-constrained communities.