Engineering Nanoscale Drug Delivery Systems for Pain

ABSTRACT

Pain is a pervasive and multifaceted condition that imposes a significant medical and economic burden worldwide. This burden is underscored by the urgent need for transformative, non‐addictive opioid alternatives. Nanomedicine offers a promising avenue for addressing the many limitations associated with conventional pain treatments, such as off‐target effects, poor bioavailability, and rapid clearance, while enabling advanced therapeutic approaches such as precise spatiotemporal control and robust delivery of biologics. In this review, we explore the convergence of nanomedicine and pain management. We examine current literature on pain and chronic pain physiology and provide collated pharmacological data on current therapeutic approaches as a reference for formulation development. Recent advancements in lipid‐based, polymeric, and inorganic nanoscale drug delivery systems (NDDS) for pain are surveyed, along with their progress toward clinical translation. Strategies for enhancing the efficacy of NDDS for pain are discussed, including supramolecular depot localization methods, active and passive targeting, controlled release kinetics, and the incorporation of stimuli‐responsive elements for triggered release. We identify knowledge and technical gaps limiting progression beyond sustained‐release formulations toward designs exploiting pain‐specific biology. Overall, this review provides a comprehensive overview of the state‐of‐the‐art in nanomedicine‐based approaches for pain management and provides a roadmap for future innovations.

Nanomedicine for pain therapy is an emerging research and translational field. This review examines pain physiology and current therapeutics, then surveys lipid, polymeric, and inorganic drug delivery systems for pain management and their clinical progress. We provide collated pharmacological data on pain drugs, discuss strategies for spatiotemporal control including depot systems and stimuli‐responsive platforms, and identify critical research gaps needed to advance transformative clinical translation.

1. Introduction

Pain serves a vital protective function, alerting us to tissue damage and harmful stimuli. However, dysregulation of this system can lead to chronic pain, which diminishes quality of life across physical, psychological, and social dimensions. In 2023 it was reported that 24.3% of adults in the United States currently suffer from chronic pain, representing a profound public health crisis and one of the most burdensome public health challenges of our time (Lucas and Sohi 2023) Moreover, the chronic pain epidemic has converged with an opioid crisis that has claimed hundreds of thousands of lives (Bohn and Raehal 2006; Volkow and Blanco 2021). Current pain management strategies remain inadequate: existing analgesics offer limited efficacy for many chronic pain conditions, carry significant risks of addiction and adverse effects, and fail to address the underlying mechanisms of pain sensitization (Hange et al. 2022). There is broad consensus among experts that the only viable long‐term solution requires the development of more effective pain therapeutics that can ultimately replace or reduce reliance on traditional opioids (Price and Gold 2018; Skolnick 2018). Novel approaches are urgently needed to address the efficacy limitations and safety concerns of current treatments.

Nanomedicine may be a promising strategy for transforming pain management. Nanoscale drug delivery vehicles (NDDS) which have at least one dimension in the nanoscale range (10–1000 nm), can address limitations of conventional pain therapies. By improving drug bioavailability, extending therapeutic windows, and enabling combination therapies and locoregional delivery, NDDS can enhance treatment efficacy while reducing systemic side effects. Active targeting functionalities can direct drugs specifically to sites of pain and inflammation, minimizing off‐target toxicities. NDDS enable comfortable and effective administration routes by protecting drugs from metabolic degradation and facilitating transport across biological barriers. These capabilities position NDDS as promising strategy for developing a new generation of pain treatments (Andreu and Arruebo 2018; Babaie et al. 2022; da Silva et al. 2022).

Additionally, there are several other aspects of pain biology that are uniquely suited to NDDS approaches, as opposed to conventional extended‐release formulations. First, despite the heterogeneity of pain presentation, the pain tissue microenvironment has common distinctions such as local acidosis, oxidative stress, and co‐involvement of sensory neurons and immune cells. This presents an opportunity for targeting and responsive delivery. Second, pain signaling heavily involves G‐protein coupled receptors (GPCRs), and there is a growing body of work showing that these receptors are internalized through endocytosis during activation (Chen et al. 2025; Tonello et al. 2023). Nanoparticles are uniquely suited to access endosomes and thus deliver therapeutics to the compartments in which the receptors are located (Ramirez‐Garcia et al. 2023).

Realizing the potential of NDDS for pain requires a holistic understanding of pain biology and nanomaterial design principles. This review provides a comprehensive examination of nanomedicine approaches for pain management. We begin by exploring pain and chronic pain physiology, establishing the biological foundation for understanding therapeutic targets. We then survey current pain pharmacology, highlighting major therapeutic targets, cataloging relevant drugs and their properties to inform formulation design. The core of the review examines recent advances in lipid‐based, polymeric, and inorganic NDDS for pain, analyzing their progress toward clinical translation. We further explore emerging strategies for enhancing NDDS performance, including depot delivery systems, targeting approaches, and stimuli‐responsive platforms for on‐demand drug release (Figure 1). Finally, we identify critical research gaps and barriers to clinical translation, offering areas for future innovations in pain nanomedicine.

FIGURE 1.

Schematic overviewing topics discussed herein. (A) Pain intervention strategies, from blocking nociception to inhibiting pain signals and reducing inflammation. (B) Highlighted nanomaterials used for pain NDDS applications including lipid, polymer, and inorganic systems. (C) Emerging strategies to further advance control of drug delivery through improved drug retention, site‐specific delivery, and responsive platforms.

1.1. Physiological Mechanisms of Pain

Pain sensation initiates when nociceptors, specialized sensory neurons with free nerve endings, detect noxious stimuli in peripheral tissues including skin, viscera, joints, and muscles. These first‐order neurons, with cell bodies located in the dorsal root ganglion (DRG), respond to diverse stimuli: mechanical nociceptors detect intense pressure and tissue damage, thermal and mechano‐thermal nociceptors sense temperature extremes, and polymodal nociceptors integrate mechanical, thermal, and chemical signals. Once activated, nociceptors transmit pain signals through afferent nerve fibers to the spinal cord, where second‐ and third‐order neurons relay these signals to the brain, thus contributing to the conscious experience of pain (Ringkamp et al. 2018).

Chemical mediators play a critical role in nociceptor activation and sensitization, representing key targets for pain therapeutics. These mediators include protein kinases (Mizumura et al. 2009), histamines (Obara et al. 2020), substance P (Jensen et al. 2017), calcitonin gene‐related peptide (CGRP) (Yarwood et al. 2017), potassium (Burnstock 2000; Chen et al. 1995), serotonin (Loyd et al. 2013), and acidic molecules such as lactic acid or low‐pH solutions (Tominaga et al. 1998; Waldmann et al. 1997). In acute pain, this signaling cascade serves its protective function; the unpleasant sensation abates once the noxious stimulus is removed or the injury heals. However, certain conditions cause this protective mechanism to turn into a pathological state.

1.2. Chronic and Neuropathic Pain

Chronic pain is a distinct pathophysiological state in which pain persists long after the original injury has resolved. This transformation from acute to chronic pain involves fundamental changes in nervous system function, creating a self‐perpetuating cycle of sensitization and inflammation. Patients suffering from chronic pain frequently develop neuropathic pain (Attal et al. 2011; Smith and Torrance 2012; Smith et al. 2007), characterized by hyperexcitability of the nociceptors and an increased inflammatory state. Neuropathic pain is clinically defined by heightened pain responses (hyperalgesia) and pain responses to generally innocuous stimuli (allodynia) (Sandkühler 2009). Patients can develop neuropathic pain from diverse conditions such as cancer, diabetes, infection, or injury, but share the common feature of a diminished quality of life which may not be resolved by standard analgesic interventions.

The transition to chronic pain is mediated by complex inflammatory processes that offer multiple targets for nanomedicine approaches. Damaged tissue releases paracrine modulators, including pro‐inflammatory cytokines and prostaglandins, that both stimulate inflammation and directly activate nociceptors, creating a bidirectional relationship between pain and inflammation. This inflammatory milieu, including microglia activation, drives sensory neuron plasticity and sensitization (Barcelon et al. 2019). Subsequent dysregulation of this polarization, particularly the balance between pro‐inflammatory M1 and pro‐regenerative M2 phenotypes, perpetuates neuropathic pain states (Chen et al. 2018; Raghavendra et al. 2003). Additionally, elevated levels of reactive oxygen species (ROS) and oxidative stress characterize the chronic pain microenvironment (Bruehl et al. 2022). Together, these suggest antioxidant and anti‐inflammation strategies as potential therapeutic interventions and nanomedicine targets. The following sections examine how current pharmacological interventions address these mechanisms and how NDDS can enhance their therapeutic efficacy.

2. Overview of Pain Pharmacological Interventions

Pain management strategies aim to relieve symptoms; due to the complexity of pain, simply inhibiting nociception is not always feasible nor effective. Biomedical interventions aim to reduce sensitization, decrease pain amplification, and restore normal pain thresholds. Current pain therapeutics can be organized into three primary intervention strategies: (1) blocking nociception at the site of detection, (2) inhibiting downstream pain signal transmission either by enhancing inhibitory pathways or blocking excitatory pathways, and (3) reducing neurogenic inflammation that perpetuates pain states. This organizational framework helps clarify where different drug classes act and illuminates opportunities for nanomedicine enhancement.

Understanding the current landscape of anti‐pain pharmacology can inform NDDS design. To guide nanomedicine scientists and engineers, we have collated relevant physicochemical and pharmacokinetic characteristics of commonly used pain therapeutics, both clinical and promising research compounds. Table 1 presents small molecule drugs with properties critical for nanoformulation design, including LogP, total polar surface area (TPSA), pKa, potency (IC50/EC50 values), and clearance rates. Table 2 catalogs biologics for pain inhibition, including peptides, antibodies, and nucleic acids. These data provide essential starting points for rational NDDS design.

TABLE 1.

Small molecule pain drugs and relevant characteristics for nanoformulation.

Analgesic mechanism	Drug	Structure	cLogP a	Molar volume a	TPSA a	pKa c	EC50 b	Half life (Hr) d	Clearance (L/Hr) d
TRPV1 agonist	Capsaicin		3.1	310.37	58.56	—	292 ± 54 nM (McNamara et al. 2005)	1.6	—
Serotonin (5HT‐1) receptor agonist	Sumatriptan		1.4	269.73	65.2	4.9	5HT‐1A: > 1000 nM 5HT‐1B: 77 nM 5HT‐1D: 4.3–220 nM	1.9	71.6
	Paroxetine		4.05	295.72	39.73	9.6–9.9 (GlaxoSmithKline 2023)	—	21	70.2
	Duloxetine		4.69	278.54	21.26	9.6–9.7	44.5 nM (Chappell et al. 2014)	12	94.7 a
	Amitriptyline		4.19	285.14	3.24	9.4	50 nM (Jang et al. 2009)	17	23.7
Mv‐opioid receptor agonist	Morphine		1.1	256.68	52.93	9.85	34–60 nM	2	97.5
	Hydrocodone		1.73	274.53	38.78	8.23	—	16	—
	Fentanyl		3.79	340.16	23.55	7.89–8.60 (Thurlkill et al. 2005)	0.510–53 nM	7	32.5
	Methadone		4.25	320.4	20.31	8.94–10.12	—	31	6.6
	Buprenorphine		4.87	449.63	62.16	8.31	0.3–21 nM	36.5	55
Cannabinoid receptor agonist	Dronabinol		6.69	323.99	29.46	10.6 (NDA 18‐651/S‐021 Dronabinol 2004)	Receptor 1: 17–78 nM Receptor 2: 1.5–12 nM	30.5	13 (NDA 18‐651/S‐021 Dronabinol 2004)

Analgesic mechanism	Drug	Structure	cLogP a	Molar volume a	TPSA a	pKa	IC50 b	Half Life (Hr) d	Clearance (L/Hr) d
	Acetaminophen		0.68	140.01	49.33	9.4–9.7 (Yoon et al. 2007)	—	2.1	17.5
Local anesthetic (sodium channel blocker)	Lidocaine		2.13	244.86	32.34	7.86–8.01	2–24 μM	1.75	57
	Bupivacaine		3.34	301.5	32.34	8.09–8.17	69.5–186 μM (Schwoerer et al. 2015; Stoetzer et al. 2017)	3.1	16.7
	Ropivacaine		2.78	284.69	32.34	8.07–8.16	255–351 μM (Schwoerer et al. 2015; Stoetzer et al. 2017)	4.2	23
NaV 1.8 inhibitor	Suzetrigine		2.88	377.91	103.55	—	0.27 nM (Vaelli et al. 2024)	23.6	13.9
Calcium channel inhibitor	Gabapentin		0.62	174.2	63.32	pKa 1: 3.7 pKa 2: 10.07 (Kasim et al. 2004)	27 nM	5.5	7.6
	Pregabalin		0.66	168.11	63.32	pKa 1–4.2 pKa 2–10.6	23 nM	6	3.7 a
Dopamine receptor antagonist (D2)	Metoclopramide		2.54	278.91	67.59	9.27–9.3	483 nM (Hirokawa et al. 2002)	5.5	22.2
	Haloperidol		4.3	336.98	40.54	8.3 (Kasim et al. 2004)	0.160–550 nM b	35	30.4
GABA receptor antagonist	Propofol		3.7	191.96	20.23	11.1	8–44 μM	3.2	150
NMDA receptor antagonist	Ketamine		2.96	218.4	29.1	7.5	0.43 ± 0.1 μM (Parsons et al. 1996)	2.8	74
NK1 receptor antagonist	Aprepitant		4.17	416.55	83.25	9.7 (Wu et al. 2004)	0.09 nM (Degnan et al. 2015)	11	4.4 a
CGRP receptor antagonist	Olcegepant		3.54	695.24	176.4	—	0.03 nM (Rudolf et al. 2005)	2.5 (Iovino et al. 2004)	12 (Iovino et al. 2004)
	Rimegepant		0.98	460.22	119.15	pKa 1: 2.1 pKa 2: 6.5 pKa 3: 9.8 (NDA‐212728 (ODT) Rimegepant 2019)	0.14 nM (Luo et al. 2012)	11	—
	Atogepant		2.92	477.41	104.29	—	0.026–0.050 nM (Moore et al. 2024)	11	19
	Zavegepant		3.19	599.24	120.67	pKa 1: 4.8 pKa 2: 8.8	0.04 nM (NDA 216386 (Zavzpret, zavegepant) 2023)	6.55	266
PAR2 antagonist	I‐343		3.32	518.60	112.39	—	0.4 nM (Jimenez‐Vargas et al. 2018)	—	—
	AZ‐3451		4.97	493.22	141.44	—	23 nM	—	—
P2X3 inhibitor	Eliapixant		3.14	392.1	86.24	—	8 nM (Davenport et al. 2021)	23.5–48.5 (Klein et al. 2022)	48.2 (Fasting Only) (Klein et al. 2022)
	A‐317491		4.97	493.22	141.44	—	> 10 nM (Jarvis et al. 2002)	—	—
	AF‐219 (Gefapixant)		0.97	296.92	156.46	—	42.6+/2.9 nM (Cui et al. 2022)	8.2–9.6 (Nussbaum et al. 2024)	7.0–10.2 (Nussbaum et al. 2024)
VEGFR antagonist	Pazopanib		3.27	377.90	119.04	pKa 1: 2.1 pKa 2: 6.4 pKa 3: 10.2 (NDA 22‐465 VOTRIENT Pazopanib 2008)	VEGFR1: 10 nM VEGFR2: 30 nM VEGFR3: 47 nM (Podar et al. 2006)	30.9	—
TrKA antagonism	Larotrectinib		2.41	364.12	86.00	—	5–11 nM (VITRAKVI (larotrectinib) n.d.)	2.9	98
NRP1 inhibitor	EG00229		−1.05	388.00	200.25	—	8 uM (Jarvis et al. 2010)	—	—
NSAID	Aspirin		1.43	155.57	63.6	3.5 (Kasim et al. 2004)	COX‐1: 3.57 μM COX‐2: 29.3 μM (Blanco et al. 1999)	0.25	27.7 a
	Ibuprofen		3.46	211.19	37.3	5.2 (Kasim et al. 2004)	COX‐1: 13 μM COX‐2: 370 μM (Noreen et al. 1998)	2	2.9
	Naproxen		3.38	213.97	46.53	4.15 (Kasim et al. 2004)	COX‐1: 8.65–1.10 μM COX‐2: 12.4–1010 μM b	14.5	0.507
	Celecoxib		3.62	298.65	77.99	11.1 (Paulson et al. 2001)	COX‐1: 8.97–15.2 μM COX‐2: 45–63 nM	11.2	27.7
	Diclofenac		4.57	238.73	49.33	3.99–4.15	COX‐1: 0.611 μM COX‐2: 0.63 μM (Blanco et al. 1999)	2.3	34.9

^a Calculated values sourced from Molinspiration Cheminformatics free web services.

^b If not specified, obtained from University of California San Diego (UCSD) Binding DB (Liu et al. 2025). This resource is a public and web‐accessible database that aggregates experimentally measured binding affinities of small molecules. Ranges for values cited from this database have been limited to only human cell binding studies for the reported analgesic mechanism for each compound.

^c If not specified, obtained from PubChem (a publicly available chemical information repository managed by the National Institutes of Health (NIH)) and The Merck Index Online.

^d Values sourced from the Cheminformatic Tools and Databases for Pharmacology database (e‐Drug3D) and from (Douguet 2018).

TABLE 2.

Biologics for pain inhibition.

Class of biologic	Molecule name	Class/mechanism	Sequence/product name(s)	Status, indication	References
Peptide	DADLE	Opioid	Tyr‐D‐Ala‐Gly‐Phe‐D‐Leu	—	(Jimenez‐Vargas et al. 2020)
	DAMGO	Opioid	H‐Tyr‐D‐Ala‐Gly‐N‐MePhe‐Gly‐ol	—	(Zhang et al. 2013)
	DPDPE	Opioid	D‐Pen2, D‐Pen5	—
	JOM‐5	Opioid	Tyr‐c[d‐Cys‐Phe‐d‐Pen]‐NH2(Et)	—
	ADAM8	Opioid	Amidino‐Tyr‐D‐Arg‐Phe‐MebAla‐ol	—	(Ogawa et al. 2002)
	LENK	Leucine enkephalin	Tyr‐Gly‐Gly‐Phe‐Leu	—	(García‐Domínguez 2024)
	MENK	Methionine enkephalin	Tyr‐Gly‐Gly‐Phe‐Met	—
	Biphalin	Dimeric enkephalin analog	Tyr‐D‐Ala‐Gly‐Phe‐NH‐NH‐Phe'‐Gly'‐D‐Ala'‐Tyr'	—	(Redkiewicz et al. 2021)
	R9‐CBD3‐A6K	CaV2.2‐CRMP2 disruption	RRRRRRRRRARSRLKELRGVPRGL	—	(Xie, Chew, et al. 2016)
	SNX‐111/ω‐MVIIA	N‐type Ca channel inhibition	H‐Cys‐Lys‐Gly‐Lys‐Gly‐Ala‐Lys‐Cys‐Ser‐Arg‐Leu‐Met‐Tyr‐Asp‐Cys‐Cys‐Thr‐Gly‐Ser‐Cys‐Arg‐Ser‐Gly‐Lys‐Cys‐NH2 Ziconotide	Approved for chronic pain intrathecal injection	(McGivern 2007)
Monoclonal antibodies	Anti‐NGF	Block NGF binding TrKA	Tanezumab Fulranumab Fasinumab	Phase 3 paused/rejected for safety concerns (2021) Arthritis pain	(Patel et al. 2018)
	Anti‐CGRP	Block CGRP binding to CLR	Eptinezumab, erenumab, galcanezumab, Fremanezumab, galcanezumab	Approved for migraine and headache treatment	(Schuster and Rapoport 2017; Wang, Wang, et al. 2022)
	Anti PAR2	Blockade of PAR2	MEDIO618	Phase 1 underway for migraine	(Kopruszinski et al. 2025)
	Anti‐TNFa	Anti‐inflammation	Remicade (infliximab), Enbrel (etanercept), Humira (adalimumab), Cimzia (certolizumab pegol) and Simponi (golimumab)	Approved for various inflammatory, autoimmune, and chronic pain conditions
	Anti IL6 receptor	Anti‐inflammation	Tocilizumab, sariluman, siltuximab	Approved for various inflammatory conditions
Nucleic acids	P2X3 siRNA	Silence purinergic receptors	—	—	(Dorn et al. 2004)
	P38 siRNA	Inhibit microglia activation	—	—	(Shin et al. 2018)
	IRF5‐siRNA	Anti‐inflammation, M1 to M2 macrophage transition	—	—	(Li et al. 2016)
	SYL‐1001‐siRNA	Silences TRPV1 expression	Tivanisiran	Phase 3 completed for ocular pain, safety demonstrated but efficacy benchmarks were not met	(Moreno‐Montañés et al. 2018; M. Zhang, Bahal, et al. 2021)
	LV‐TNF‐shRNA1‐4	Silences TNFa	—		(Ogawa et al. 2014)

2.1. Blocking Nociception

This intervention strategy targets nociceptors directly, either preventing their activation or blocking the ion channels essential for transmitting signals from peripheral tissues to the spinal cord. By intervening at this earliest stage of pain processing, these drugs can prevent pain signals from ever reaching the central nervous system.

2.1.1. TRP Channel Modulation

Transient receptor potential (TRP) channels, particularly TRP‐vanilloid‐1 (TRPV1), are first line detectors of noxious stimuli, and thus are of interest in pain therapy. TRPV1 agonism, via capsaicin for example, paradoxically reduces pain through receptor desensitization. The activation of TRPV1 induces the internalization and downregulation of the receptor, temporarily preventing pain signaling (Ann et al. 2020). This approach has shown clinical promise in treating cancer pain via intrathecal resiniferatoxin, an ultrapotent agonist (Mannes et al. 2025). Antagonizing TRPV1 may also be a promising strategy. However, while TRPV1 antagonists, such as competitive inhibitor capsazepine, have demonstrated preclinical efficacy, no small molecule antagonists have achieved commercial approval (Koivisto et al. 2022).

A major issue with TRPV1 modulation is thermal dysregulation; many studies in animals and humans have shown hyperthermia and heat sensitivity as side effects with antagonism and hypothermia/heat insensitivity with agonism. This is a known on‐target side effect, driven by altered signal transmission of sensory neurons to the central nervous system, but independent of neuropeptide release (Yue et al. 2022). This significant issue will need to be bypassed through designing antagonists that avoid calcium release, or by hyper‐localized delivery of the antagonist.

RNA interference (RNAi) technology offers an alternative strategy for TRPV1 inhibition. Short interfering RNA (siRNA) targeting TRPV1 reduces receptor expression on nerve fibers, mitigating both acute pain sensation and hyperalgesia. Tivanisiran, a nanocarrier‐free siRNA formulation, has made progress in clinical trials for post‐operative ocular pain and dry eye disease (Benitez‐Del‐Castillo et al. 2016; Moreno‐Montañés et al. 2018).

Other TRP channels present additional therapeutic opportunities. The TRPV4 receptor senses mechanical stress and can be sensitized to drive mechanical hyperalgesia. The selective TRPV4 blocker GSK2193874 has shown efficacy in preclinical models of chronic pain, including orofacial cancer pain, though clinical development continues (Cheung et al. 2017; Peng et al. 2022).

2.1.2. Sodium Channel Inhibition

Nonselective sodium (NaV) channel blockers such as lidocaine and bupivacaine are cornerstone local anesthetics that block pain perception by preventing the sodium influx required for action potential generation in sensory neurons. While these drugs offer fast acting and safe pain relief, they exhibit poor half‐life, low bioavailability, and cardiotoxicity; thus, they are clinically used for local numbing and short time frame anesthesia (Schwoerer et al. 2015). Additionally, the lack of specificity toward relevant NaV subtypes makes numbing and loss of motor function significant side effects.

Among nine mammalian NaV isoforms, NaV1.7, NaV1.8, and NaV1.9 show nociceptor‐specific expression, making them attractive targets for pain inhibition without motor side effects. However, close structural homology across isoforms has historically made selective drugging challenging. A breakthrough came in 2025 with the FDA approval of suzetrigine, a first‐in‐class non‐opioid analgesic targeting NaV1.8. Suzetrigine was found to have sub‐nanomolar potency and high selectivity for NaV1.8, with in vitro electrophysiology results showing a 31,000‐fold selectivity ratio of NaV1.8 over the other subtypes (Osteen et al. 2025; Vaelli et al. 2024). It was also shown to be effective in treating moderate to severe acute pain following oral administration, with ongoing trials for neuropathic pain applications.

Another strategy for NaV channels that has shown promise involves interrupting protein–protein interactions, thus producing analgesia while avoiding direct channel blockade (Cai et al. 2021).

Gene therapy is also gaining a foothold in pain treatment. Epigenetic repression of NaV1.7 using CRISPR‐dCas9—an inactivated “dead” Cas9 that does not permanently edit the genome—has shown remarkably long lasting analgesia in mice models of neuropathic pain (Moreno et al. 2021).

2.2. Inhibiting Downstream Pain Signals

Once nociceptors are activated, pain signals propagate centrally through neurotransmitter release and receptor activation. The second major intervention strategy targets these downstream signaling cascades. This can be achieved through two complementary approaches: enhancing endogenous inhibitory pain pathways or blocking excitatory pain signaling pathways. These strategies attenuate pain without preventing initial nociceptor detection of tissue damage.

2.2.1. Enhancing Inhibitory Pathways

2.2.1.1. Opioid Receptor Agonism

Opioid receptor agonists enhance the body's natural pain inhibition systems, acting at multiple levels of the nervous system. These drugs primarily work by activating receptors that suppress neurotransmitter release from afferent neurons, effectively increasing the “gain” on endogenous pain control mechanisms (São Pedro et al. 2016). Among the opioid receptor family which include mu‐, delta‐, kappa‐type, the mu‐opioid receptor (MOR) is the primary target for potent analgesia (Valentino and Volkow 2018). Opioids such as morphine, codeine, oxycodone, and fentanyl provide effective pain relief but carry severe risks: respiratory depression, constipation, addiction, and tolerance with prolonged use. These side effects have driven the opioid epidemic and underscore the urgent need for safer alternatives (Ehrlich et al. 2019). Endogenous opioid peptides such as DADLE and DAMGO exhibit selectivity for delta‐opioid receptors (DOR) over MOR, potentially offering analgesia with reduced side effect profiles, due to the improved selectivity, but still exhibit adverse effects at high doses (Jimenez‐Vargas et al. 2020). These short peptides also exhibit rapid enzymatic degradation and poor bioavailability (Roques et al. 2012), limiting their clinical utility without advanced delivery strategies. Gene therapy approaches to induce enkephalin production have also shown preclinical success, achieving more localized activity of the peptide (Hao et al. 2003).

2.2.1.2. Cannabinoid Receptor Agonism

Drugs targeting cannabinoid receptors are promising alternatives to opioids. Activation of cannabinoid receptors, especially CB1 and CB2, leads to downregulation of neuronal excitation and modulation of serotonergic and noradrenergic pathways. Several CB1/2‐targeting drugs have been developed, particularly for relief of neuropathic pain as analgesics for patients with advanced cancer (Sainsbury et al. 2021). These compounds offer different side effect profiles compared to opioids, potentially providing safer long‐term pain management options (Onaivi et al. 2020; Vučković et al. 2018).

2.2.2. Blocking Excitatory Pathways

2.2.2.1. Calcium Channel Inhibition

Calcium channel blockers prevent the release of excitatory neurotransmitters that propagate pain signals. Gabapentinoids, gabapentin and pregabalin, represent first‐line treatments for moderate neuropathic pain by inhibiting voltage‐gated calcium channels (CaV) (Chincholkar 2018; Finnerup et al. 2015). While these drugs show favorable efficacy‐to‐side‐effect ratios compared to many other pain medications, they still produce metabolic, cardiac, and neurological adverse effects that limit their use (McKeever and Hamilton 2022). Introducing selectivity for blocking N‐type CaV (CaV2.2) isoforms over others has had success in treating pain while reducing side effects (Gao et al. 2021; McCleskey et al. 1987). This is most evident in the clinical success of the peptide inhibitor ziconotide; however, its use is still limited due to the low therapeutic index and the requirement for intrathecal administration, which has low tolerability in some patients (McGivern 2007). Similarly to NaV channels, inhibiting CaV2.2 interactomes has also been effective (Allen et al. 2024).

2.2.2.2. Neurokinin‐1 Receptor Antagonism

Neurokinin‐1 receptor (NK1R) is activated by substance P and amplifies pain cascades. Several NK1R antagonists have been developed including Vofopitant, Casopitant and Orvepitant, but have shown limited efficacy for pain in humans (Hill 2000). Aprepitant, a commercial NK1R antagonist used to prevent chemotherapy‐induced nausea, has also shown limited pain efficacy (Chizh et al. 2007; D'Amico et al. 2025). However, NK1R is endocytosed in response to substance P mediated nociception, and specific antagonization of the receptor in endosomes via lipid‐drug conjugates or via nanoparticle delivery has produced sustained and effective pain relief (Jensen et al. 2017; Latorre, Ramírez‐Garcia, et al. 2022; Mai et al. 2021). This finding suggests that targeted delivery of NK1R antagonists to endosomal compartments could unlock their therapeutic potential.

2.2.2.3. Calcitonin Receptor‐Like Antagonism

Calcitonin‐like receptor (CLR) antagonists block the binding of neurotransmitter CGRP, inhibiting the downstream pain signal cascade. Several antagonists belonging to this class have been developed to treat patients suffering from migraines. Currently, rimegepant (Pan et al. 2020) and zavegepant (Ahmed et al. 2024) are two approved small molecule CLR antagonists on the market, and two others, olcegepant and umegepant, have been studied (Recober and Russo 2007; Schuster and Rapoport 2017). CLR is endocytosed upon activation, similar to NK1R, and that NDDS‐mediated delivery of olcegepant to endosomes has enhanced and prolonged antinociceptive effects (Peach et al. 2025; Yarwood et al. 2017).

Monoclonal antibodies targeting CLR or circulating CGRP are also clinically successful. Fremanezumab, Eptinezumab, Galcanezumab, and Erenumab (Table 2) have been approved for migraine treatment and prevention (Nicol and Burkett 2025).

2.2.2.4. Protease‐Activated Receptor 2 Antagonism

Protease‐activated receptor type 2 (PAR2) has been implicated in inflammation and chronic pain, including osteoarthritis and inflammatory bowel syndrome (Jimenez‐Vargas et al. 2018; Kennedy et al. 2020). Several drug candidates are undergoing first‐in‐human clinical trials, with one monoclonal antibody in development (Kopruszinski et al. 2025), though none have achieved approval. Recent evidence shows that, like NK1R and CLR, PAR2 signals from endosomes, suggesting that targeting strategies may enhance therapeutic efficacy (Bhansali et al. 2025; Jimenez‐Vargas et al. 2018; Latorre, Hegron, et al. 2022).

2.2.2.5. Purinergic Receptor Antagonism

Purinergic receptor P2X3 is an ATP‐gated ion channel expressed on sensory neurons that contributes to pain signaling. By blocking ATP‐mediated activation of nociceptors, P2X3 antagonists work to alleviate pain, particularly in conditions where ATP release contributes to chronic pain states (Chen et al. 1995). Eliapixant is a selective P2X3 receptor antagonist that has shown promise in clinical trials for chronic cough and is being investigated for pain applications (Davenport et al. 2021).

2.2.2.6. Vascular Endothelial Growth Factor (VEGF) Inhibition

Vascular endothelial growth factors (VEGF) are a sub‐family of growth factor proteins involved in vasculogenesis and angiogenesis. Clinical evidence shows that patients with chronic pain have increased levels of VEGF‐A in their synovial fluid, correlating with higher pain scores (Takano et al. 2018). VEGF‐A promotes sensory neuron hyperexcitability through interaction with neuropilin 1 (NRP1) (Jarvis et al. 2010). Blocking this signaling axis reduces chronic neuropathic pain in preclinical models, suggesting VEGF pathway inhibition as a novel pain target (Stratton et al. 2023). Small molecule VEGF receptor antagonists like pazopanib, originally developed for cancer, are being explored for pain applications (Ma et al. 2023).

2.2.2.7. Tropomyosin Receptor Kinase A Antagonism

Tropomyosin Receptor Kinase A (TrKA) a receptor tyrosine kinase and co‐receptor for nerve growth factor (NGF), is another promising target. Anti‐NGF monoclonal antibodies reduce both acute and chronic pain by blocking NGF binding to TrKA and preventing receptor internalization and downstream pain signaling. Tanezumab, developed by Pfizer and Eli Lilly for arthritis pain, was paused in 2021 due to safety and efficacy concerns, though related antibodies (fulranumab, fasinumab) continue in development (Patel et al. 2018). Recently, neuropilin‐1 was found to be a coreceptor and facilitator for the TrKA/NGF axis, offering an alternate drugging strategy that may avoid the detriments of direct NGF blockade (Peach et al. 2024).

2.3. Reducing Neurogenic Inflammation

The third major intervention strategy addresses the inflammatory dysregulation that perpetuates chronic pain states. Reducing inflammation not only addresses pain‐adjacent injury and disease states, but also interrupts the positive feedback loop between inflammation and nociceptor sensitization, which is critical in chronic and neuropathic pain states.

2.3.1. Nonsteroidal Anti‐Inflammatory Drugs

Nonsteroidal anti‐inflammatory drugs (NSAIDs) are the most commonly administered pain relievers for pain and inflammation, working by inhibiting cyclooxygenase enzymes (COX1 and COX2). COX2 expression is induced during pain and inflammation, making it the primary therapeutic target. While commonly taken orally, NSAIDs exhibit poor water solubility, short half‐lives, and off‐target toxicities including gastrointestinal bleeding and cardiovascular risks. These compounds are well‐studied model drugs for NDDS development, yielding improved outcomes in vitro and in vivo while potentially reducing systemic side effects (Guilherme et al. 2019; Janjic et al. 2018; Lopes‐de‐Araújo et al. 2016).

2.3.2. Prostaglandins E2 Receptor Antagonism

Prostaglandins are produced in response to tissue damage and mediate both pain and inflammation. Prostaglandins E2 (PGE2) acts through four receptor subtypes (EP1‐EP4), with EP2 showing particular relevance to neuroinflammation. Recent findings show that EP2 receptor knockdown attenuates neuroinflammation without completely blocking peripheral inflammation, suggesting specific targeting of neural PGE2 signaling as a viable strategy (Nassini et al. 2025). EP2 antagonist candidates PF‐04418948 and TG6‐10‐1 have shown preclinical efficacy in reducing mechanical allodynia in mouse endometriosis models, demonstrating the potential of this approach for inflammatory pain conditions (Ganesh 2023; Greaves et al. 2017).

2.3.3. Corticosteroids

Corticosteroids such as dexamethasone and triamcinolone are potent anti‐inflammatory agents commonly prescribed for pain and inflammation. These drugs act through multiple mechanisms including suppression of pro‐inflammatory cytokine production and inhibition of immune cell activation (McEwen and Kalia 2010). However, systemic corticosteroid use carries significant risks including immunosuppression, metabolic disturbances, and tissue breakdown with prolonged administration (Salerno and Hermann 2006). Localized delivery via nanomedicine approaches could enhance their safety profiles by concentrating drug at sites of inflammation while minimizing systemic exposure (Simón‐Vázquez et al. 2022).

2.3.4. Modulating Inflammation With Biologics

Biologic therapies targeting pro‐inflammatory cytokines are powerful tools for managing inflammatory pain. Antibodies against tumor necrosis factor alpha (TNFα)—including infliximab, etanercept, adalimumab, certolizumab pegol, and golimumab—are FDA‐approved for various inflammatory and autoimmune conditions and show promise for relieving chronic pain associated with numerous inflammatory comorbidities (Zhang, Shi, et al. 2021). Similarly, anti‐interleukin‐6 (IL‐6) receptor antibodies such as tocilizumab, sarilumab, and siltuximab address inflammatory cascades that contribute to pain (Kelkar et al. 2024).

RNAi has also been used in immune applications for pain. Short hairpin RNA (shRNA) targeting TNFα expression in DRG has demonstrated analgesic effects in preclinical models (Ogawa et al. 2014). Similarly, siRNA targeting inflammatory signaling molecules such as p38 and IRF5 have shown efficacy in modulating microglial activation and macrophage polarization, addressing the neuroimmune dysregulation that characterizes chronic pain states (Li et al. 2016). Nucleic acid therapeutics require protection from degradation and targeted delivery to relevant cell types, challenges that nanomedicine is particularly well‐positioned to address (Shin et al. 2018).

An alternative to inhibiting pro‐inflammatory molecules is enhancing expression of anti‐inflammatory molecules. This strategy has shown to be successful with IL‐10 gene therapy via plasmid delivery in osteoarthritis in dogs (Watkins et al. 2020) and with IL1Ra, which is currently being tested clinically for osteoarthritis pain using an AAV‐based delivery (Nixon et al. 2018; Snuggs et al. 2025).

3. Current Status of NDDS for Pain

3.1. Classes of NDDS

The application of nanomedicine to pain management has generated substantial preclinical research across diverse material platforms and drug classes. Understanding the current landscape of pain‐focused NDDS requires examining the major nanocarrier types, their unique advantages for pain applications, and their progress toward clinical implementation. While reductive, classifying NDDS by primary material composition—lipid, polymeric, and inorganic—helps identify trends and opportunities in pain‐specific applications.

Table 3 provides a comprehensive survey of recent literature organized by nanocarrier type and drug class, offering a reference for researchers developing new pain NDDS. Local anesthetics and NSAIDs dominate the landscape across nanocarrier type as the more common drug classes to be formulated. Lipid‐based nanoparticles dominate the earlier literature, but works in the last 5 years are overtaken by polymer nanoparticles. Lipid nanoparticles show strength in biologic encapsulation, but polymer nanoparticles, inorganic nanoparticles, and hybrid types are increasing in development and show an increasing variety of drug classes. Many types of administration routes have been studied, but local injection and transdermal/topical application remain the most attractive and successful in pain applications. The most common animal models of pain and neuropathic pain utilize physical or chemically induced nerve damage—chronic constriction injury (CCI), nerve ligation, or inflammatory pain (via complete Freunds adjuvant, or carrageenan). Osteoarthritis models are also very common, and there is emerging use of colitis, corneal pain, cancer pain, and endometriosis pain models. Increased usage of CGRP antagonists is of note as well.

TABLE 3.

Highlighted NDDS for pain in recent literature, by NDDS type and drug type.

NDDS type	Drug class	Carrier/material	Drug/bioactive	In vivo/preclinical pain model	Administration route	Notes/points of interest	References
Lipid	Local anesthetics	PEGylated Liposomes	Bupivacaine	Cancer pain	Local injection	Targeting tumor innervation	(Kaduri et al. 2021)
		Liposome	Ropivicaine	Post‐operative pain	Local injection	HIP improved loading and efficacy	(Ke et al. 2022)
		LNP	Ropivicaine	Neuropathic pain (spared nerve injury, chemotherapy‐induced)	Intravenous	Active targeting of DRG	(Sun et al. 2025)
		SLN in cellulose membranes	Lignocaine Diclofenac	Pre‐ and post‐op dental pain	Intraoral	Multidrug loaded Transmucosal patch	(Malviya et al. 2015; Nidhi et al. 2016)
		NLC	Butamben	Inflammatory pain (carrageenan)	Local injection	pH responsive to local acidosis	(Rodrigues da Silva et al. 2021)
		Liposomes	Lidocaine Cannabidiol	Local neuropathic pain	Transdermal	Co‐loading, CBD fluidizing effect	(Franzè et al. 2022)
	NSAIDs	NLC	Ibuprofen	Ocular pain	Eye drop Oral	Thermo‐responsive release	(Almeida et al. 2017)
			Naproxen	Inflammatory TMJ pain	Intra‐articular injection	Sustained release, high encapsulation efficiency	(Guilherme et al. 2019)
			Oxaprozin	Inflammatory Pain	Oral	Macrophage targeting	(Lopes‐de‐Araújo et al. 2016)
		SLN hydrogels	Ibuprofen	Localized pain and inflammation	Transdermal	Hydrogel depot	(Pham et al. 2020)
		Niosome emulgel	Piroxicam	Osteoarthritis pain	Transdermal	Reduction in pain scores in humans compared to free piroxicam	(Masjedi et al. 2025)
	Opioids	Liposomes	Loperamide	Inflammatory pain	Intravenous	Targeted brain delivery using ICAM‐1 Ab functionalization	(Hua and Cabot 2013)
		LNP	Morphine	Neuropathic pain (CCI)	Intravenous	Targeted delivery to DRG using Tet1	(Yang et al. 2024)
		SLN	LP2 (delta‐mu opioid antagonist)	n/a	n/a	Novel API – synthetic opioid	(Spadaro et al. 2021)
	Biologics	PEGylated SLN	TRPV1 siRNA	Acute and neuropathic pain	Topical and local injection	RNA delivery	(Sharma et al. 2018)
		LNP	BDNF siRNA	Neuropathic pain	n/a	RNA delivery	(Dave et al. 2021)
Lipid		Squalenoylated prodrug micelle	Leu‐Enkephalin	Inflammatory pain (carrageenan)	Intravenous	Prodrug extended release/inflammation accumulating	(Feng et al. 2019)
		LNP	Modified NGF mRNA	Paclitaxel‐induced neuropathy	Local injection	Expression of modified non‐nociceptive NGF	(Yu et al. 2023)
	Purinergic receptor antagonist	Chitosan‐coated NLC	A‐317491	Endometriosis pain	Intravenous	Targeting endometrial lesions	(Yuan et al. 2017)
	Other	SLN	Vitexin	Peripheral neuropathy	Intraperitoneal	Natural product formulation	(Eken et al. 2024)
Polymer	Local anesthetics	PCL in Carbopol Hydrogel	Lidocaine/Prilocaine	Dental pain	Intraoral topical	NPs‐in hydrogels improved efficacy	(Muniz et al. 2018)
		PCL	Lidocaine	Nerve block	Local injection		(Ramos Campos et al. 2013)
		PCL	Lidocaine, chloramphenicol	Post‐operative pain	Intraoral	Drug‐eluting biomembrane	(Vasconcelos et al. 2022)
		PLGA	Benzocaine	Sciatic nerve block	Local injection	Use of oil co‐excipient improved loading and release rate	(de Melo et al. 2011; Moraes et al. 2009; Silva De Melo et al. 2012)
		Chitosan/PLGA in poloxamer	Benzocaine	n/a	Topical	Thermosensitive hydrogel matrix	(Campos et al. 2022)
	NSAIDs	PEG–PLA	Ibuprofen	n/a	Intravenous	Brain delivery using polysorbate 80	(Zhang, Chau, et al. 2021)
		PNIPAM	Indomethacin	n/a	n/a	Thermoresponsive release	(Constantin et al. 2017)
		PEGylated PLGA	Dexibuprofen	Corneal pain	Ocular	Improved retention and permeation in the cornea	(Sánchez‐López et al. 2016)
		Chitosan‐ poly(methacrylic acid)	Diclofenac	n/a	n/a	Drug‐polymer complexation	(Duarte Junior et al. 2017)
Polymer		Perfluoropolyether nanoemulsion	Celecoxib	Inflammatory/cancer pain	Intravenous	Theranostic/multimodal imaging	(Patel et al. 2013; Saleem et al. 2019)
	NSAIDs	Drug nanoparticles in PVA/PVP hydrogel	Diclofenac	Chronic pain	Transdermal	Nano‐in‐micro approach improved skin permeation, systemic bioavailability	(Li, Vora, et al. 2024)
		PEG–PLA	Ibuprofen	n/a	n/a	Improved encapsulation efficiency with sequential nanoprecipitation	(El Amri et al. 2025)
	Opioids	PLA, PLGA	Fentanyl	Postoperative pain	Subcutaneous	Extended release polymer‐drug conjugate	(Kovaliov et al. 2017)
		PLGA‐PEG‐PLGA	Loperamide	n/a	Intravenous	Surfactant coating for brain delivery	(Chen et al. 2011)
		PEG‐PLGA, shellac	Ketamine	Cancer pain	Intravenous	Hierarchical, no effect on release or PK	(Han et al. 2020)
	Cannabinoid	PLGA	D9THC	Neuropathic pain	Oral	Long lasting pain relief	(Berrocoso et al. 2017)
	NK1R Antagonist	PEGMA‐DIPMA	Aprepitant	Chronic and inflammatory pain	Intrathecal	pH responsive, neuronal endosome targeting	(Latorre, Ramírez‐Garcia, et al. 2022)
	NaV, CaV blocker	PLGA‐PVA	Lamotrigine	Neuropathic Pain (partial sciatic nerve injury)	Intravenous	Brain targeting via lactoferrin‐transferrin functionalization	(Lalani et al. 2015)
	Anti‐inflammatory	PLGA	Fexofenadine	Neuropathic pain	Intrathecal	Microglia targeting, drug re‐orienting	(Tran et al. 2022)
	Serotonin Receptor agonist	PLGA‐poloxamer	Zolmitriptan	Migraine	Oral	Blood–brain barrier crossing	(Girotra et al. 2016)
	SNRI	PLGA	Duloxetine	Neuropathic pain (sciatic nerve ligation)	Intrathecal	Microglia targeting, drug re‐orienting	(Kim et al. 2021)
	Biologics	PLGA	P38 siRNA	Neuropathic pain	Intrathecal	Microglial targeting	(Shin et al. 2018)
		PLGA‐PEG/PEI	NGF siRNA	Chemotherapy induced peripheral neuropathic pain	Intravenous	Multimodal‐inhibition of tumor innervation	(Zuo et al. 2024)
		Chitosan	DADLE	n/a	n/a (in vitro only)	Endosomal escape of biologic, uptake in neurons	(Malatesta et al. 2014)
Polymer		PEG‐PLGA	CBD3‐A6K	Neuropathic pain (CCI)	Intraneural	Encapsulation of peptide, long lasting analgesia (16 days)	(Zhang et al. 2026)
		PLGA	Plasmid DNA (IL‐4, IL‐10, TGFb1)	Neuropathic pain (sciatic nerve transection)	Intrathecal	Encapsulation of plasmid DNA for gene delivery	(Choi et al. 2025)
	PAR2 antagonist	PAMAM dendrimer	AZ3451	Oral cancer pain	Intratumoral	Endosomal target/delivery	(Bhansali et al. 2025)
		PAMAM dendrimer, PEG–PLA	AZ3451	Ulcerative colitis pain	Enema	Comparison of two types of NDDS	(Teng et al. 2025)
	VEGFR antagonist	PEG‐PCL	Pazopanib	Osteoarthritis pain	Intraarticular injection	8 weeks pain and symptom relief; no comparison with free drug	(Ma et al. 2024)
	CLR antagonist	PEG–PLA	Olcegepant	Oral cancer pain	Intratumoral	Ion pairing approach improved encapsulation, endosomal receptor targeting	(Peach et al. 2025)
		PLGA/PVA	Ubrogepant	Migraine (nitroglycerin)	Intranasal, intravenous	Improved AUC, half‐life, compared to free drug formulation	(Mohan and Pethe 2026)
	Other	PLGA	Acetominophen	Pain at high altitudes	Intranasal	Intranasal enabled brain delivery and delayed elimination	(Huang et al. 2025)
Inorganic	N/A	Iron oxide	n/a	Chronic inflammatory pain	Local injection	Mild analgesic effect	(Wu et al. 2017)
		Zinc oxide	n/a	Local anesthesia	Local injection	Mild analgesic effect	(Cui et al. 2020)
		Molybdenum Disulfide Gold Nanorods	n/a	Osteoarthritis pain	Subcutaneous injection	Theranostic, active targeting using anti‐NGF Ab	(Au et al. 2021)
		Gold‐ruthenium Nanozyme	n/a	Neuropathic pain (CCI)	Intravenous	ROS‐scavenging and inflammation inhibition, mitochondria targeting	(Cheng et al. 2025)
		Metal‐polyphenol nanoparticle	n/a	Discogenic pain	Intrathecal	Antioxidant, macrophage polarity targeting to enhance mitochondrial transfer to nerves	(Wang, Guo, et al. 2025)
	NSAID	Cu‐based MOF	Ibuprofen	n/a	n/a (in vitro only)	pH sensitive microsphere depot	(Javanbakht et al. 2019)
		Fe‐based MOF	Diclofenac	n/a	n/a (in vitro only)	pH sensitive release	(So et al. 2020)
	Local Anesthetics	Hybrid graphene oxide nanogels	Lidocaine	Sciatic nerve block	Topical	Sustained release up to 10 h	(Li et al. 2021)
		Hollow silica nanoparticle	Tetrodotoxin	Perpiheral nerve block	Local Injection	Uptake in neurons investigated	(Liu et al. 2018)
		Cerium oxide‐based MOF	Bupivicaine	Neuropathic pain	Local injection	Combined anti‐inflammatory and ROS scavenging	(Wang, Ji, et al. 2025)
		Liposome‐coated MSN	Levobupivicaine	Post‐operative pain and inflammation	Local injection	Liposome coating improved efficacy, intrinsic anti‐inflammation	(Qiao et al. 2024)
		MSN	Lidocaine	n/a (human ex vivo)	Transdermal	Cationic surface functionalization to improve skin permeation	(Nafisi et al. 2018)
		Silica coated gold nanorod/MSN	Ropivicaine	Nerve block	Local injection	Improved duration over free drug, photothermal induced release	(Wang, Zhang, et al. 2021)
	TRPV1 agonist	PLGA‐coated iron oxide	Capsaicin	Inflammatory pain	Local injection	Site‐specific targeting	(Baskaran et al. 2017)
	CGRP antagonist	Hybrid PEGylated iron oxide, cerium oxide MSN	Olcegepant	Neuropathic pain (CCI)	Local injection plus magnetic targeting	Site specific magnetic targeting	(Tian et al. 2025)
	Biologics	MSN	miR‐26a‐5p (microRNA)	Chronic pain	Intrathecal	Active targeting of microglia	(Lu et al. 2024)
		MSN	ARA290, Δ9‐tetrahydrocannabinol	Neuropathic pain (CCI)	Intraperitoneal	Redox‐responsive release, synergistic co‐loading	(Xie, Chew, et al. 2016)
		Zeolitic imidazolate MOF/Iron oxide	Superoxide dismutase	Inflammatory pain (CFA)	Intrathecal	Reducing oxidative stress in microglia	(Ling et al. 2023)

Novelty in recent publications comes from dual‐loading and multimodal approaches, therapeutic carriers, active targeting, and formulation of biologics such as siRNA and gene editing machinery. The increasing breadth and scope in terms of drug classes and pain models examined demonstrate the developing landscape of pain nanomedicine.

3.1.1. Lipid‐Based Systems

Lipid‐based NDDS, including liposomes, solid lipid nanoparticles (SLNs), and nanostructured lipid carriers (NLCs), exhibit excellent biocompatibility and represent the most clinically advanced nanomedicine platform. The ability to encapsulate both hydrophobic and hydrophilic drugs has made lipid NDDS particularly attractive for pain applications where prolonged tissue retention may be required, such as injury requiring local anesthesia or NSAID.

Liposomes are bilayer vesicles with an aqueous core that can entrap water‐soluble drugs while incorporating lipophilic compounds within the bilayer. This dual‐compartment architecture is valuable for pain therapeutics, where drugs with divergent solubility profiles may need to be co‐delivered together. This approach has been successfully demonstrated with local anesthetics, opioids, and biologics (Martinez et al. 2024). For local anesthetics, liposomal encapsulation addresses a critical limitation: extending anesthesia duration beyond the 2–4 h achieved with free drug. The passive diffusion‐controlled release from liposomes can prolong regional anesthesia to 8–12 h or more, reducing the need for repeated injections (Chahar and Cummings 3rd. 2012).

Multivesicular liposomes (MVLs) represent a specialized architecture with multilamellar compartments created through sequential emulsion processes. These 10–30 μm structures contain nanoscale lipid and aqueous compartments that enable high drug loading and sustained release (Chaurasiya et al. 2022). Moreover, their large size enables locoregional tissue retention. MVLs have been used to deliver clinically to prolong the efficacy of local anesthetics and reduce post‐surgical opioid use. Clinical success of liposomal and MVL NDDS is discussed in detail in section 3.2.

Solid lipid nanoparticles (SLNs) can offer more control over nanocarrier size and release properties relative to liposomes, but lack an aqueous core (Paliwal et al. 2020). Work by Sharma et al. demonstrated the first encapsulation of TRPV1 siRNA in SLNs without cationic components through high pressure cold homogenization (Sharma et al. 2018). The SLNs achieved cellular transfection and silencing of TRPV1 in vitro. Topical administration in rats produced effective thermal analgesia over 24 h, compared to ineffective free nucleic acid, demonstrating the potential for nucleic acid delivery to sensory neurons.

Nanostructured lipid nanocarriers (NLCs) are second‐generation lipid nanoparticles incorporating both solid and liquid lipid regions, enabling greater drug loading capacity and tunable release kinetics (Khan et al. 2023). Guilherme et al. developed NLCs loaded with the NSAID naproxen for intraarticular administration and treatment of temporomandibular joint pain. A near‐complete encapsulation efficiency of naproxen was achieved, with a sustained release profile which improved the in vivo efficacy (Guilherme et al. 2019). Importantly, these formulations maintained shelf stability for one year—a critical consideration for clinical translation where storage stability often determines commercial viability.

3.1.2. Polymeric Systems

Polymeric nanoparticles offer favorable stability and a wide range of tunable chemical and mechanical properties, making them highly versatile platforms for pain NDDS. The extensive toolkit of polymer chemistry enables precise control over drug loading, release kinetics, and surface functionalization (Hwang et al. 2020).

Solid polymer matrix‐based nanocarriers, particularly poly(lactide‐co‐glycolide) (PLGA) formed by emulsion methods, are among the most widely used formulations. In pain applications, PLGA nanoparticles have successfully delivered opioids, cannabinoids, anesthetics, and anti‐inflammatory drugs (Berrocoso et al. 2017; Kim et al. 2021; Moraes et al. 2009; Phạm and Kim 2020; Shin et al. 2018; Silva De Melo et al. 2012). Incorporating cationic poly(ethyleneimine) (PEI) components enables complexation with negatively charged nucleic acids. This was shown recently with NGF siRNA, in which authors Zuo et al. utilized co‐loaded doxorubicin and NGF siRNA PLGA nanoparticles to treat chemotherapy‐induced peripheral neuropathy. This co‐delivery approach inhibited pain by both limiting tumor innervation, and by reducing downstream pain signaling (Zuo et al. 2024).

Core‐shell polymeric nanoparticles consist of a hydrophobic core and a hydrophilic shell, typically formed from amphiphilic block copolymers. Flash Nanoprecipitation (FNP), a continuous flow precipitation process, has been used to successfully encapsulate ibuprofen and the VEGF receptor antagonist pazopanib (Ma et al. 2024; Zhang, Chau, et al. 2021). Recently, FNP enabled high‐efficiency encapsulation of the PAR2 antagonist AZ3451, producing nanoparticles with sustained release over several days. When delivered colonically, these nanoparticles effectively reduced pain in mouse models of ulcerative colitis by accessing endosomal PAR2 receptors, outperforming free drug that had proven ineffective (Teng et al. 2025). This example illustrates how NDDS can rescue ineffective compounds by enabling delivery to specific subcellular compartments.

Polymer dendrimers, that is, highly branched and functionalizable polymers, can entrap and carry diverse therapeutics through both encapsulation and surface conjugation (Wang, Li, et al. 2022). For pain applications, poly(amidoamine) (PAMAM) dendrimers with cholesterol have been used to deliver a PAR2 antagonist through endosomal targeting, achieving effective pain relief in oral cancer models (Bhansali et al. 2025).

A distinct advantage of polymeric nanoparticles is stability; nanoparticles can withstand gastrointestinal conditions and penetrate gut mucosa, especially when formulated with dense PEG brush surfaces (Bannunah et al. 2014; Date et al. 2016; Yuan et al. 2013). Berrocoso et al. demonstrated this capability with oral PEGylated PLGA nanoparticles encapsulating a cannabinoid derivative, achieving sustained neuropathic pain relief for 11 days in rodents (Berrocoso et al. 2017).

3.1.3. Inorganic‐Based Systems

Inorganic nanomaterials possess unique optical, chemical, and physical properties that enable multimodal pain therapeutics. These materials can function simultaneously as drug carriers, imaging agents, and therapeutic agents themselves, expanding the possibilities for pain management beyond simple drug delivery (Huang et al. 2020).

Gold nanoparticles are easily functionalized and are multifunctional as imaging and therapeutic agents. In a neuropathic pain application, functionalized gold nanorods enabled biodistribution monitoring via photoacuoustic imaging, and near‐infrared excited phototherapy provided therapeutic functionality. This integration of targeting, imaging, and therapy showcases the multimodal potential of inorganic platforms (Au et al. 2021).

Mesoporous silica nanoparticles (MSN) are a well‐established inorganic NDDS with high surface area enabling substantial drug loading through surface adsorption. These particles are easily functionalized and have shown good tolerability and safety in proof‐of‐concept studies for oral delivery (Bukara et al. 2016). In pain applications, MSNs have been used to deliver local anesthetics, GPCR antagonists, cannabinoids, peptides and proteins (Nafisi et al. 2018; Tian et al. 2025; Wang, Zhang, et al. 2021; Xie, Xiao, et al. 2016). For example, hollow silica nanoparticles with physically entrapped tetrodotoxin, a potent sodium channel inhibitor with poor bioavailability and short half‐life, improved circulation time to nearly 48 h and enhanced neuronal uptake, demonstrating how high‐capacity carriers can enable delivery of drugs that would otherwise be clinically unusable (Liu et al. 2018). MSNs exhibit rapid drug release, which has prompted the use of hybrid platforms, such as bupivacaine‐loaded MSN with a liposome coating. The coating both slowed the in vitro release of the drug and extended the analgesic efficacy of the drug from 6 (free) and 12 h (uncoated) to 18 h (Qiao et al. 2024). This strategy was also effective with bio‐derived membranes (Qiao et al. 2023).

Metal organic frameworks (MOFs) are inorganic polymer‐like nanostructures that have higher surface area and pore size than MSNs, enabling higher drug loading capability (Lawson et al. 2021). MOFs are an emerging platform for controlled pain therapeutic delivery (Mendes et al. 2020; So et al. 2020). Interestingly, MOFs have also shown pH dependent release rates, with slow drug release in acidic gastrointestinal conditions and faster release at neutral pH. This shows promise for gastrointestinal stability, making MOF‐based NDDS potential candidates for oral delivery of pain therapeutics (Javanbakht et al. 2019, 2018).

Inherent analgesic properties of certain inorganic nanoparticles add an additional dimension to their therapeutic utility. Iron oxide and zinc oxide, for example, were shown to have mild analgesic effects in mice, which has been attributed to the metal oxide's ability to reduce reactive oxygen species (ROS) and inhibit macrophage activation (Cui et al. 2020; In Choi et al. 2013; Wu et al. 2017). Inherently antioxidizing or anti‐inflammatory inorganic vehicles can be used to achieve multimodal pain inhibition. For example, Ling et al. developed a hybrid MOF‐type NDDS incorporating superoxide dismutase enzyme. The inorganic compounds were intended to enhance the catalytic antioxidative activity of the enzyme, and in vivo experiments demonstrated that the NDDS accumulated in the inflamed spinal cord tissue and provided analgesia through microglia inactivation (Ling et al. 2023). Similarly, a cerium‐based MOF loaded with bupivacaine was recently reported that exhibits both sustained analgesic effects as well as anti‐inflammation. It was found that the MOF scavenged ROS in vitro, and while the vehicle alone provided some reduced pain, the combined therapy administered via local injection achieved 36 h of pain relief in a chronic constrictive injury model of neuropathic pain (Wang, Ji, et al. 2025). These examples illustrate a key advantage of inorganic NDDS: the carrier itself can be therapeutic, not just a delivery vehicle. For chronic pain where oxidative stress and neuroinflammation are central pathological features, antioxidant and anti‐inflammatory carrier materials may provide therapeutic benefit complementary to drug payload.

3.2. Commercial NDDS

Nanomedicine for pain management is an emerging field with limited but growing clinical presence. Currently, only three FDA‐approved NDDS formulations exist for pain in the United States (Table 4): Diprivan, Exparel (Pacira Biosciences), and DepoDur (Pacira Biosciences) (Anselmo and Mitragotri 2019). All are lipid‐based, extended release formulations of anesthetics or opioids (Chahar and Cummings 3rd. 2012). Approved in 1989, Diprivan is a propofol‐loaded lipid nanoemulsion administered intravenously for sedation and anesthesia. DepoDur and Exparel, both developed by Pacira Biosciences using proprietary DepoFoam MVL technology, provide extended‐release delivery of morphine and bupivacaine, respectively (Mantripragada 2002; Richard et al. 2011). The DepoFoam technology has been shown to exhibit superior extended‐release profiles lasting several days to a week when injected subcutaneously (Salehi et al. 2020). Liposomal morphine in the DepoDur formulation is intended for epidural administration and has been shown to have a more favorable pharmacokinetic profile than free morphine, with a max blood plasma concentration (C_max) reduction of 70%, and with an extended‐release profile (Gambling et al. 2005). Initially approved in 2004, DepoDur manufacturing has since been voluntarily discontinued for strategic reasons.

TABLE 4.

Commercial pain NDDS in the US.

Product name	Status	Formulation	Indication	Administration route
Diprivan	FDA approved (1989)	Lipid emulsion propofol	Induction and maintenance of sedation or anesthesia	Intravenous
DepoDur (Pacira Biosciences)	FDA approved (2004)	Liposomal morphine (DepoFoam)	Pain relief following major surgery	Epidural injection
Exparel (Pacira Biosciences)	FDA approved (2011)	Liposomal bupivacaine (DepoFoam)	Postsurgical analgesia in adults	Local injection/nerve block

While Exparel has been approved for use in regional pain since 2011, studies since then have contested whether single dose liposomal bupivacaine has significantly better efficacy than free local anesthetic. While consistently achieving statistically significant improvements in therapeutic indices, pain scores, and reduction in opioid rescue use, Exparel has repeatedly failed to meet thresholds of clinical relevance in several recent meta‐analyses (Chen et al. 2023; Hussain et al. 2024; Saad Sayed et al. 2025). Essentially, improvements in patient experience compared to standard free bupivacaine were of trivial magnitude. Additionally, tissue injury and increased injection inflammation has been reported (McAlvin et al. 2014). These, combined with the substantially higher costs of liposomal bupivacaine relative to free drug, make it an unfavorable choice for clinicians and patients (Ilfeld and Sessler 2024). As pain nanomedicine matures, opportunities exist to address unmet clinical needs where current therapies are inadequate rather than incrementally improving existing solutions.

3.3. Progress in Clinical Trials

Clinical development of pain NDDS is actively expanding, with several formulations in late‐stage trials (Table 5). This growing pipeline reflects increasing recognition of nanomedicine's potential for pain management. Liposomal formulations lead the clinical pipeline. TLC599 (liposomal dexamethasone) completed Phase 3 trials for chronic knee osteoarthritis pain, targeting sustained intraarticular delivery of anti‐inflammatory corticosteroids. TLC590 (liposomal ropivacaine) is in Phase 3 trials for post‐surgical pain, building on the sustained‐release local anesthetic concept established by DepoFoam technology.

TABLE 5.

Pain NDDS in clinical trials.

Product name	Clinical trial information	Formulation	Indication	Administration route
Exparel (Pacira Biosciences)	Phase 4 ID NCT03737604 Recruiting	Single dose liposomal bupivacaine vs. ropivacaine continuous infusion	Post‐operative pain after renal transplant	Ultrasound guided transversus abdominis plane (TAP) block
	Phase 1 ID: NCT05456490	Safety and evaluation of intrathecal administration	n/a	Single intrathecal injection
PCRX‐201 (Pacira Biosciences)	Phase 2 ID NCT06884865 Active/Recuiting	Gene therapy (AAV) delivery of inducible IL1Ra	Painful osteoarthritis of the knee	Single knee injection
TLC599 (TLC Biosciences)	Phase 3 complete ID: NCT04123561	Liposomal dexamethasone	Moderate to severe chronic knee pain due to osteoarthritis	Intraarticular injection
TLC590 (TLC Bioscience)	Phase 2/3 ID NCT05161637 Not yet recruiting	Multilamellar vesicular ropivicaine	Postsurgical pain	Local injection
NanaBis (Medlabs)	Phase 3 ID: NCT04808531 Unknown status	Nanoparticle formulation of d9‐THC and CBD	Opioid‐requiring bone pain due to metastatic cancer	Oro‐buccal spray
DexNP (OCS‐01)	Phase 2 ID: NCT04130802 Completed, Results available	Dexamethasone Cyclodextrin nanoparticle	Post‐operative ocular pain and inflammation after cataract surgery	Eye drop
AuNP	ID: NCT05347602 Phase 1–3 Recruitment completed	Aqueous suspension of AuNPs 8‐28 nm diameter	Knee pain, and arthritis	Oral
Capsaicin Nanoparticle Gel	Phase 2/3 ID: NCT01125215 Status unknown	Capsaicin nanoparticle gel	Diabetic Neuropathic Pain	Topical cream
AeroLEF (YM Biosciences)	Phase 2 completed/on hold ID: NCT00286065 ID: NCT00791804 Completed	Aerosolized liposomal fentanyl	Acute pain/Acute post‐operative pain	Oro‐buccal spray

Note: Information obtained from clinicaltrials.gov or from company websites.

Notably, alternative routes and drug classes are also being explored. For example, an oro‐buccal nanoparticle spray of cannabinoids (D9‐THC and CBD) reached Phase 3 trials for metastatic cancer bone pain. This formulation bypasses first‐pass metabolism and extends analgesic effects. Phase 2 data showed reduced C_max with increased duration and AUC compared to free drug, enabling dose reduction (Clarke et al. 2020). Several topical formulations are in early trials, including dexamethasone‐cyclodextrin nanoparticles for ocular pain (Phase 2 completed) and capsaicin nanoparticle gel for diabetic neuropathic pain (Phase 2/3). PCRX‐201 (Pacira Biosciences) recently began Phase 2 trials using AAV vectors to deliver inducible IL‐1 receptor antagonist for osteoarthritis pain, highlighting NDDS‐enabled gene‐based pain therapeutics (Snuggs et al. 2025).

Exparel continues post‐approval development with Phase 4 trials comparing it to continuous anesthetic infusion and Phase 3 evaluation in pediatric populations. As of 2025, Phase 1 trials have initiated for intrathecal administration and chronic pain applications, seeking to identify clinical scenarios where sustained release provides compelling advantages.

This expanding clinical pipeline, while still modest compared to other therapeutic areas, reflects the field's growth. The diversity of platforms (liposomes, cyclodextrin complexes, cannabinoid nanoparticles), routes (injection, topical, oro‐buccal), and targets (acute post‐surgical pain, chronic inflammatory pain, neuropathic pain, cancer pain) suggests researchers are exploring multiple paths to address different unmet needs in pain management. As this emerging field matures, identifying which specific pain conditions and patient populations benefit most from nanomedicine approaches will be critical for advancing clinical translation.

4. Advancing Spatiotemporal Control of Pain Drug Action

As evidenced above, there is a disconnect between preclinical efficacy of NDDS for pain and realized market success. This disconnect—which is not unique to the pain subfield—combined with the post‐approval findings regarding liposomal bupivacaine do not rule out NDDS for pain as a concept nor negate the evidence of efficacy described in this review. Instead, it suggests the need for a vertically integrated approach to formulation design, where manufacturing scale‐up and production costs are kept in mind from the onset. These challenges are discussed in section 5. Additionally, it suggests a difficulty with translating NDDS that utilize well‐established therapeutics in standard application, such as local anesthetics for nerve block; since these therapies already perform well as free drug formulations, incremental improvements in efficacy through NDDS approaches will not make enough of a difference to offset the development costs.

Additionally, for drug profiles that would benefit solely from extended release, non‐NDDS strategies, such as bulk implants, osmotic pumps or transdermal patches, may be more cost effective, as these strategies have already been found to be effective clinically for opioids and anesthetics (Jones et al. 2016). NDDS can be used instead to transform otherwise failed drug candidates into viable therapies and expand options beyond opioids and anesthetics, thus enabling meaningful improvements in patient care.

It is necessary to advance the level of control over pain drug action to move from incremental to transformational improvements. In the latter half of this review, we will focus on advanced strategies for precision drug delivery and strategies that may help enable the advancement of pain NDDS. Herein, we detail emerging strategies for improving drug loading, controlling release rates, improving localization, and incorporating responsive release platforms.

4.1. Improving Drug Encapsulation and Retention

By increasing entrapment of the drug within the carrier or slowing vehicle disassembly, drug concentrations in tissue or plasma can be maintained for longer. Sustained activity from NDDS, particularly for targeting downstream pain pathways and inflammation, or for pain drugs with poor half‐life, shows potential for maintaining therapeutic drug concentrations for longer, reducing drug toxicity and dosage frequency.

4.1.1. Prodrug and Drug‐Carrier Conjugate Strategies

Prodrugs are molecules that undergo a transition into a bioactive form once metabolized in the body, and are common throughout the pharmaceutical landscape (Stella 2010). When coupled with a NDDS, a prodrug approach can improve the loading and slow the release kinetics of water soluble and weakly hydrophobic small molecule drugs. This strategy is well established, and has been demonstrated with buprenorphine, which was shown to continuously release from LNPs in its hydrophobic prodrug form (Wang et al. 2009). More recently, for polymeric NDDS, a palmitate moiety conjugated to dexamethasone increased its loading capability in PLGA‐PEG nanoparticles from 0.2% to 7.5%. The pro‐dexamethasone nanoparticles improved pain and inflammation scores and in a mouse arthritis model, reversing symptoms to baseline compared to free dexamethasone injections (Figure 2A).

FIGURE 2.

Examples of anti‐pain NDDS strategies for hydrophilic drugs (A) Palmitoylating dexamethasone (DXP) enabled encapsulation into polymeric nanoparticles (DXP‐NP), which provided greater relief than free drug (DSP) in a mouse model of arthritis. Adapted from (Simón‐Vázquez et al. 2022) with permission (B) Squalenoylated leucine‐enkephalin molecules self assembled into micelles(LENK‐SQ NP). The NDDS achieved pain reversal compared to ineffective free peptide (LENK) and could be inhibited using opioid antagonists (Nal, Nal‐M). Adapted from (Feng et al. 2019) under a Creative Commons CC BY NC license (C) Triamcinolone conjugated to PAMAM dendrimers yielded small nanoparticles (D‐TA) that outperformed free drug (TA) in reversing mechanical allodynia in a peripheral nerve injury model. Adated from (Kim et al. 2017) under a Creative Commons CC BY NC 3.0 license (D) HIP of olcegepant and pamoic acid enabled greater encapsulation efficiency of the drug into polymeric nanoparticles (FL‐OCP‐NP), and achieved greater analgesic effects than free olcegepant (OCP) in a mouse model of oral cancer pain. Adapted from (Peach et al. 2025) under a Creative Commons CC BY 4.0 license.

Feng et al. developed a novel self‐assembling prodrug strategy for peptide delivery (Feng et al. 2019). By conjugating squalene, a bio‐derived lipid, to leucine‐enkephalin, an endogenous opioid, they created a prodrug molecule that micellized into 60–120 nm nanoparticles. These prodrug NDDS showed sustained pain relief profiles in inflammatory pain, with similar profiles to morphine. At equivalent dosages, the free enkephalin showed no pain reduction. Additionally, the authors identified a structure–function relationship with the prodrug moiety; linking the rate of release of enkephalin to the biodistribution of the NDDS, which corresponded to in vivo efficacy (Feng et al. 2019; Lepetre‐Mouelhi et al. 2024) (Figure 2B).

Drug‐polymer conjugates are another strategy to improve entrapment within matrices. This was achieved with fentanyl by using a derivative of the drug as an initiator for PLA and PLGA polymerization. Subsequent fentanyl‐loaded nanoparticles showed mitigated burst release. In vivo, single dose fentanyl NDDS provided 6 days of pain relief (Kovaliov et al. 2017). However, it is still unclear to what extent a prodrug‐NDDS approach mitigates the safety risks of fentanyl, including issues of tolerance and addiction. In another example, triamcinolone was conjugated to a PAMAM dendrimer‐based carrier, achieving reversal of peripheral nerve injury‐induced mechanical allodynia for up to three days (Kim et al. 2017) (Figure 2C).

Several polymer‐drug conjugation methods using ibuprofen have also been reported (Wang et al. 2014). Li et al. (2018) report an ibuprofen‐conjugated diblock‐copolymer nanomicelle synthesized via reversible addition fragmentation transfer (RAFT) polymerization that was used to co‐deliver the NSAID with doxorubicin for enhanced antitumor and anti‐inflammatory effects (Li et al. 2018; Zhao et al. 2016).

4.1.2. Solubility Engineering Strategies

Hydrophobic ion pairing (HIP) is a solubility‐based formulation approach used to enhance encapsulation and modulate the release of ionizable drugs (Dimiou et al. 2023; Pinkerton et al. 2013; Ristroph and Prud'homme 2019). This technique involves complexing an ionizable therapeutic molecule with a hydrophobic counter ion, yielding a hydrophobic complex salt. This strategy has been shown to both increase encapsulation efficiency and slow drug release of small molecules, peptides, and therapeutic enzymes (Joseph et al. 2021; Lu et al. 2018; Song et al. 2016). HIP was recently used to encapsulate CLR‐antagonist olcegepant into core‐shell polymeric nanoparticles. Using counter ion pamoic acid, they achieved nearly 50% encapsulation efficiency, increased from 11% without ion pairing. When administered intratumorally in a mouse model of oral cancer pain, the NDDS displayed a 5‐fold increase in efficacy AUC compared to free drug, outperforming in both magnitude and duration of pain reversal (Peach et al. 2025) (Figure 2D).

The HIP strategy has also been used successfully in liposomes, as well as MVL to encapsulate a variety of therapeutic small molecules within the lipid bilayer (Noh et al. 2022; Oliveira et al. 2017; Phan et al. 2019; Ren et al. 2018; Tan et al. 2024; Xu et al. 2017; Zhang, Wang, et al. 2021). Ke et al. developed a ropivacaine liposomal formulation using sodium oleate as the counter‐ion for prolonged local analgesia. Using HIP, they formed liposomes with high encapsulation efficiency, and prolonged analgesic effect compared to a standard ropivacaine liposome in a sciatic nerve block model (Ke et al. 2022).

4.2. Improving NDDS Localization

4.2.1. NDDS Supramolecular Depots

Establishing a depot of NDDS can prolong drug retention and release, achieve improved locoregional delivery, and reduce systemic toxicities (Feitosa et al. 2019; Pinkerton et al. 2014). This type of spatiotemporal control can be valuable for cases of localized pain, to apply a sustained nerve block, or to address rapid drug clearance from a target tissue. As an example, MVLs can be considered a supramolecular NDDS and have been shown to be effective at locoregional analgesic delivery via subcutaneous delivery (Shen et al. 2011). Release profiles of MVLs are triphasic, with an initial small burst release, followed by release and reorganization of the compartments, and finally slow release via erosion of compartments. Similar to clinically used liposomal bupivacaine formulations, MVL formulation of ropivacaine has exhibited entrapment efficiency of 90% and in vitro drug release over 60 h. Subcutaneous delivery of the formulation showed a 35% reduction in C_max and a 3‐fold increase in AUC of blood plasma concentration compared to free ropivacaine, demonstrating that improved PK profiles and localized depots translate to prolonged analgesia (Figure 3A) (Chaurasiya et al. 2022; Manna et al. 2019; Shen et al. 2011).

FIGURE 3.

Examples of strategies for depot delivery of anti‐pain NDDS (A) MVL depots containing ropivicaine (RP‐MVL) exhibit a multistage release profile and sustained plasma concentrations over 48 h when delivered subcutaneously. Adapted from (Shen et al. 2011) with permission (B) Nanoparticles containing local anesthetics embedded in carbopol hydrogels (CNLP) achieved longer analgesia duration in topical intraoral delivery than free drug in hydrogel alone (CLP) or commercial product EMLA. Adapted from (Muniz et al. 2018) under the terms of the Creative Commons CC‐BY license (C) Diclofenac nanoparticles embedded in microneedle patches (DCF‐NP‐MN) achieved efficient drug permeation, maintained blood plasma concentration profiles longer than oral diclofenac, and exhibited skin retention at 24 and 72 h. Adapted from (Li, Vora, et al. 2024) under the terms of the Creative Commons CC‐BY license.

NDDS depots can also be achieved by embedding nanoparticles into porous hydrogel matrices (Jiang et al. 2020). Nanoparticles‐in‐hydrogels, as well as nanoparticle‐hydrogel superstructures, can be seen as hierarchical drug release systems, with both the particle and the matrix acting as diffusion barriers. Hydrogel NDDS have been used for topical intraoral delivery of anesthetics. Lidocaine and prilocaine were coloaded in PCL‐based nanoparticles and incorporated into mucoadhesive poly(acrylic acid) (Carbopol) hydrogels. The hybrid system exhibited superior release rates and in vivo analgesic profiles than both free drug in hydrogel samples and a commercial topical anesthetic (Figure 3B) (Muniz et al. 2018). For these systems, both carrier and drug release rate is dependent on the porosity of the gel, as shown recently in an anesthetic NDDS‐gel formulation (Zhang et al. 2025).

Thermoresponsive hydrogels add a layer of control through in situ gelation of a depot. Seo et al. demonstrate this type of system, showing that intraarticular injection of a thermoresponsive gel containing corticosteroid‐loaded polymeric nanoparticles provided long term local anti‐inflammatory effects in arthritic rat models (Seo et al. 2022). Thermoresponsive gels are also useful for ocular, intraoral, and transdermal delivery due to their mucoadhesive properties; delivery of NSAIDs and local anesthetics through this method has been demonstrated (Almeida et al. 2017; Campos et al. 2022).

Membrane‐based matrices are useful for depot delivery at mucosa (Vasconcelos et al. 2022). Nidhi et al. recently utilized cellulose‐based transmucosal patches entrapping SLNs coloaded with analgesic and anesthetic drugs for pain management in dental procedures. They achieved in vivo anesthesia and 24‐h lasting pain relief at the surgical site (Malviya et al. 2015; Nidhi et al. 2016).

Transdermal delivery of nanoparticles bypasses first pass metabolism, and for pain applications, it is a noninvasive method to improve locoregional specificity. However, efficient permeation through skin is a challenge. In this area, microneedle‐based delivery is promising. Combining NDDS with a dissolving hydrogel microneedle has been used in several pain NDDS (Alimardani et al. 2021). Notably, diclofenac nanoparticles delivered via microneedle patch yielded drug plasma concentrations above the IC₅₀ for 48 h, more than doubling that of oral delivery, and retained drug in the skin for over 72 h (Li, Vora, et al. 2024) (Figure 3C).

4.2.2. Active Targeting of Biological Actors in Pain

Active targeting involves decorating the nanocarrier with moieties that enable preferential accumulation in specific tissues, cell types, or organelles. Active targeting has had mixed success in fields such as cancer nanomedicine due to the interference of the protein corona, ligand shedding, and inefficacy with regards to tumor penetration (Farshbaf et al. 2022; Kirpotin et al. 2006). In pain applications, active targeting may be promising. Table 6 lists recently used strategies for pain‐targeted NDDS, by method, target, and therapeutic agent. For example, Au et al. utilized anti‐NGF antibody functionalization to actively target inflamed cartilage regions, taking advantage of both increased blood flow and higher levels of NGF in the diseased joint (Au et al. 2021). Therapeutic molecules can also act as targeting ligands, such as the case with enkephalins and other opioid agonists, as the drugging target is on the surface of the intended cell target. While GPCR agonists are known to enhance nanoparticle internalization (Hild et al. 2010), their roles as primarily excitatory molecules in pain prevents their use as active target ligands.

TABLE 6.

Active and passive targeting strategies for pain NDDS.

Type	Targeting method	Target site (tissue or cell)	Therapeutic	References
	Hyaluronan	CD44+ cells	MANF	(Li, Zhou, et al. 2025)
	Folate	Macrophages	Oxaprozin	(Lopes‐de‐Araújo et al. 2016)
			Dexamethasone/photothermal therapy	(Li, Chen, et al. 2025)
				(Lv et al. 2025)
	MG1 peptide	M1 microglia	microRNA	(Lu et al. 2024)
	Tet1	DRG	Morphine	(Yang et al. 2024)
	ADAM8	DRG	Ropivacaine	(Sun et al. 2025)
	Lectin (IB4)	DRG axon terminals via skin	n/a	(Katiyar et al. 2021)
	Lactoferrin/transferrin	Brain	Lamotrigine	(Lalani et al. 2015)
	Apolipoprotein E	Inflamed peripheral neurons	n/a	(Trumbull et al. 2025)
	Rabies glycoprotein‐based peptide RVG29	Peripheral neurons	n/a	(Trumbull et al. 2025)
Antibody	Anti‐NGF mAb	Inflamed joint tissue	Photothermal therapy	(Au et al. 2021)
Physico‐chemical (passive)	Chitosan	Ectopic endometrium	P2X3 receptor antagonist	(Yuan et al. 2017)
		Skin permeation	Lidocaine	(Nafisi et al. 2018)
		Central nervous system	DADLE	(Malatesta et al. 2014)
		Brain via intranasal	Acetaminophen	(Khanna et al. 2025)
	Size	Macrophages/microglia	Fexofenadine	(Tran et al. 2022)
	Cholesterol/lipid content	Sensory neurons and Schwann cells	n/a	(Lee et al. 2013)
		Tumor innervating neurons	Bupivicaine	(Kaduri et al. 2021)
	Polysorbate coating	Brain via blood–brain barrier	Loperamide	(Chen et al. 2011)
	Triphenylphosphine	Mitochondrial matrix	Au‐Ru nanozyme	(Cheng et al. 2025)

Sensory neurons, due to their prominent role in pain and their expression of target receptors, are one desirable target cell. Several surface ligands for active targeting have been explored specifically for DRG. Opioid receptor ligands including Tet1 and enkephalin analogs have recently shown to be effective in targeting injured and inflamed DRG (Yang et al. 2024). In particular, BK1361, an ADAM8 inhibitory peptide, enhanced systemic delivery of ropivicane LNP to injured DRG, and improved pain relief compared to non‐targeted LNPs (Sun et al. 2025). Katiyar et al. (2021) achieved targeting of peripheral DRG axons by combining skin permeation with isolectin functionalization to target purinergic receptors. Additionally, they show nanoparticles transported to the DRG cell bodies through a retrograde transport mechanism (Katiyar et al. 2021).

Another approach is to actively target immune cells involved in maintaining the painful and neuropathic environment. Folate surface‐functionalization has been used to facilitate preferential uptake by immune cells (Lopes‐de‐Araújo et al. 2016). This strategy was successful for Tran et al. (2022) who prolonged neuropathic pain relief in rats using spinal‐microglia targeting PLGA nanoparticles (Tran et al. 2022). Similarly, Lu et al. (2024) recently developed a miRNA loaded NDDS targeting microglia for long‐lasting analgesia for chronic pain. Surface‐modified MSNs modified with MG1 peptide, for M1 microglia affinity, were loaded with microRNA miR‐26a‐5p and provided pain‐relief duration of 6–7 weeks—2 weeks longer than non‐modified MSN delivery—and provided effect analgesia for inflammatory pain and chemotherapy‐induced peripheral neuropathic pain in a mouse model (Lu et al. 2024).

4.2.3. Passive Targeting

Passive targeting takes advantage of the natural accumulation of NDDS based on physicochemical properties, such as size and surface charge. These properties impact biodistribution and cellular uptake, and thus, efficacy. To illustrate this, Weldon et al. compared the local delivery of small 15 nm bupivacaine‐loaded nanoparticles to larger 100 nm liposomal bupivacaine. While the larger nanoparticles exhibited a slower release rate, the small formulation exhibited faster uptake in cells in vitro and better tissue retention in vivo, leading to anesthesia that lasted twice as long as equivalent doses of the large nanoparticles (Weldon et al. 2019). Size‐based screening can also be a tool for immune cell targeting; macrophages and microglia can phagocytose larger nanoparticles in the 200 nm‐plus diameter range, which is typically too large for endocytosis‐mediated internalization. PLGA nanoparticles in this size range formed through nanoemulsions have demonstrated use in pain and inflammation therapeutics (Shin et al. 2018; Tran et al. 2022).

Natural biopolymers such as chitosan and alginate are favorable in aiding tissue‐specific accumulation of NDDS due to their biocompatibility and mucoadhesive properties. Chitosan‐based NDDS have demonstrated reduced uptake by the mononuclear phagocytic system, thereby increasing circulation time and tissue penetration capabilities (Malatesta et al. 2014). Glycopolymer‐like chitosan nanoparticles were recently developed by Yuan et al. to target ectotopic endometrial lesions. When delivered systemically, the P2X3 receptor antagonist‐loaded nanoparticles showed more accumulation into ectopic endometrial lesions and longer pain relief compared to uncoated NDDS in a mouse model of endometriosis (Moses et al. 2021; Yuan et al. 2017).

4.3. Strategies for On‐Demand Drug Release

Stimuli‐responsive NDDS allow therapeutic delivery upon direct external manipulation via clinically translatable modalities such as light, heat, or ultrasound (Wang and Kohane 2017). These technologies enable on‐demand and site‐specific analgesia particularly suited for post‐operative recovery and injury‐rehabilitation where drug delivery can be patient‐directed. For fast acting potent anesthetics or analgesics, active control over drug delivery may mitigate the risk of systemic accumulation, off‐target toxicity, and drug dependence while preserving the utility of high‐risk therapeutics. Externally‐triggered NDDS are designed with stimuli‐responsive sensitizers that are either encapsulated within or conjugated to the nanocarrier, enabling the release of entrapped drug upon stimulus administration.

4.3.1. Light‐ and Heat‐ Responsive Platforms

Light‐responsive NDDS (LR‐NDDS) have the potential to provide tailored, on‐demand therapy as dosage can be controlled via exposure location, time, power, and beam area (Moreno et al. 2026; Yun and Kwok 2017). LR‐NDDS systems have shown efficacy in producing multiple‐stage anesthetic events using photosensitizers (e.g., porphyrins, phthalocyanines, Ir(III) complexes, Au(III) complexes) or organic chromophores (e.g., o‐nitro‐benzyl, quinoline, indoline, azobenzene, coumarin) triggered via light stimulation (Klán et al. 2013; Lan et al. 2019; Wang et al. 2023). For example, Zhang et al. (2020) introduced a coumarin‐based macromolecular prodrug poloxamer which released a tetracaine via a photo‐cleavable coumarin linkage. They demonstrated a modulated response using a low‐power light‐emitting diode (LED) for nerve block events in the rat hind paw lasting 15 min and repeatable up to 5 times (Zhang et al. 2020).

LR‐NDDS responsive to UV–Visible irradiation (200–800 nm) are often limited to epidermal‐level treatments because of light scattering in tissue depths below 1 cm (Fomina et al. 2012). Near‐infrared (NIR) light (800–2500 nm) can be a suitable alternative to UV as it offers deeper tissue penetration (1–3 cm) and improved biocompatibility (Tibbitt et al. 2010). Rwei et al. (2015) developed a tetrodotoxin (TTX)‐loaded NIR‐triggered liposomal particle containing a ROS‐forming sensitizer where irradiation at 730 nm led to peroxidation of liposomal lipids, allowing for drug release (Figure 4A). Combining responsive platforms and depot systems, Chen et al. (2017) described a phototriggered polymeric microneedle system containing NIR absorbers and lidocaine. Lidocaine delivered by the implanted microneedles was rapidly absorbed into the blood circulation within 10 min and had a bioavailability of at least 95% relative to the subcutaneous injection, showing that the proposed system could elicit a rapid onset of pain relief (Chen et al. 2017).

FIGURE 4.

Examples of LR‐NDDS for on‐demand pain management. (A) Tetrodotoxin‐loaded liposomes (TTX) with incorporated photosensitizer caused liposomal disruption upon NIR‐irradiation and allowed for light‐triggered drug release and on‐demand analagesia, repeatable three times for 24 h total. Adapted from (Rwei et al. 2015), with permission. (B) Buprenorphine‐loaded MSNs containing upconversion nanoparticles and photosensitizers (UCNPs@mSiO2‐Azo‐BH) embedded in microneedle patches enabled on‐demand transdermal delivery via NIR irradiation. The NDDS reversed thermal and mechanical allodynia. Adapted from (Han et al. 2024) with permission. (C) Photothermal triggered release of bupivicaine from nanogels. Nearly 90% drug release upon irradiation was achieved through photothermal cyclin. Adapted from (Alejo et al. 2022) under the Creative Commons CC‐BY‐NC‐ND license.

Achieving adequate penetration depth and improving photoconversion efficiencies are challenges at odds with each other; however, upconversion nanoparticles (NIR‐absorbing inorganic nanomaterials capable of anti‐Stokes emission wavelengths) offer an alternative. Han et al. (2024) developed NIR light‐responsive NDDS‐microneedle patches based on an upconversion system to control buprenorphine dosage to treat neuropathic pain. The microneedle patches contained nanoparticles emitting blue light upon NIR excitation, which were coated with mesoporous silica, loaded with drug, and sealed with a reversible photo‐isomerizable molecular trigger. The microneedle patch performed 168% higher than a hydrogel group and 53% higher in traditional microneedle group in terms of drug penetration ratios. Tests in a controlled cortical impact model in mice showed that the treatment restored thermal and mechanical pain thresholds (Han et al. 2024) (Figure 4B).

As an alternative strategy, some LR‐NDDS utilize photosensitizers capable of converting optical energy into thermal energy for NDDS disruption. Prieto et al. (2022) recently designed a long‐lasting bupivacaine‐loaded thermoresponsive nanogel, comprised of hollow gold nanoparticles coupled to poly(oligoethylene glycol methacrylate), activatable by NIR irradiation. Drug release was repeatedly induced due to the thermally triggered, reversible deswelling/swelling nature of the nanogel at 38°C. When co‐delivered with dexamethasone, the anesthetic effect was triggerable via irradiation 48 h after administration in rats (Prieto et al. 2022). Alejo et al. (2022) used a similar approach via encapsulated bupivacaine nanocrystals into oligo(ethylene glycol)methyl ether methacrylate thermoresponsive nanogels coupled to NIR‐absorbing biodegradable copper sulphide nanoparticles. Upon NIR irradiation, a single complete burst release of bupivacaine nanocrystals was achieved from the NDDS (Alejo et al. 2022) (Figure 4C).

4.3.2. Release via Ultrasound Cavitation

Ultrasound is an alternative non‐invasive external stimulus with deeper tissue‐penetrating capability than light. Ultrasound waves propagate through tissue and induce cavitation, which can be advantageously used to induce drug release (Qiao et al. 2022; Sirsi and Borden 2014). Rwei et al. (2017) demonstrated the ultrasound‐triggered delivery of tetrodotoxin from liposomes by way of sonosensitizer protoporphyrin IX (PPIX). After the initial 8‐h nerve block due to passive drug release, the anesthetic effect could be repeated twice after ultrasound insonation in rats (Rwei et al. 2015). Song et al. (2022) recently designed dendritic MSNs with perfluoropentane and levobupivacaine to achieve repeatable on‐demand anesthesia. Ultrasound irradiation initiated a liquid‐to‐gas transition of perfluoropentane, where the vaporization disrupted the interaction between levobupivacaine and the nanocarrier. Sciatic nerve injections into mice showed continuous analgesia for more than 9 h after repeated ultrasound irradiation, 3‐fold longer than free drug injection (Song et al. 2022). As a follow‐up, Qiao et al. (2023) created coated NDDS which enabled triggerable pain reduction for up to 3 days and ultrasound‐enhanced pain relief over 20‐fold greater than with free drug (Qiao et al. 2023) in an incision pain mouse model. Most recently, Song et al. (2025) coated the dendritic MSNs with Rg3‐liposome coating as a means to reduce drug leakage and enhance stability achieving repeated pain modulation twice without shortening the analgesic duration (Song et al. 2025).

4.4. Responsive Strategies Within the Pain Microenvironment

Microenvironment‐responsive NDDS are a promising strategy that allows for precise control of drug release without the need for an external trigger. Like on‐demand release platforms, these NDDSs contain sensitive moieties either as part of the nanocarrier or as a pro‐drug form. However, these systems release drug in response to an endogenous environmental cue. This allows for spatiotemporal release of drug only in the pain and inflammation microenvironment, eliminating the need for external stimuli.

4.4.1. pH‐Responsive Release

Local variation in pH is a robust stimulus, either as localized acidosis at the site of pain, or as the acidic subcellular compartments of endolysosomes. pH responsive NDDS can have sensitive moieties in the carrier itself, as a prodrug, or as a co‐excipient. The first strategy is commonly used in the form of acid sensitive polymer linkages or ionizable side groups (Dou et al. 2020; Gao et al. 2010; Wang, Wang, et al. 2021).

NDDS deformulation at low pH enables drug release within acidic endosomes—which are implicated in pain signaling due to the internalization of GPCRs (Jensen et al. 2017; Jimenez‐Vargas et al. 2020, 2018). Recently, aprepitant, a potent NK1R antagonist, was encapsulated within a polymeric micelle comprised of a hydrophobic core and an ionizable PEGMA‐co‐DMAEMA. Upon decrease in pH from 7.4 to 6.0, deprotonation of the DMAEMA group caused micelle destabilization and cargo release. The nanoparticles were shown to colocalize with early and late endosomes and internalized NK1 receptors. In intrathecal administration of the NDDS in a capsaicin‐induced preclinical model of acute pain, the pH sensitive NDDS outperformed non‐responsive ones and free drug in terms of pain relief intensity, and exhibited a greater efficacy AUC than morphine (Figure 5A) (Ramírez‐García et al. 2019).

FIGURE 5.

Responsive release strategies. (A) pH responsive NDDS (DIPMA) deformulated in acidic conditions. DIPMA nanoparticles containing aprepitant (DIPMA‐AP) relieved neuropathic pain for over 4 h, doubling the duration and magnitude of free drug (AP) and non‐responsive nanoparticles (BMA‐AP) Adapted from (Ramírez‐García et al. 2019) with permission. (B) ROS‐responsive ibuprofen polymer micelles (MBTA‐IBU) disassembled in the presence of hydrogen peroxide and reduced inflammatory cytokine expression in activated macrophages in vitro. Adapted from (Quek et al. 2022) with permission. (C) MSNs loaded with Ara290 and d9THC (“nanocomplex”) exhibited Ara290 release in the presence of DTT, and restored pain thresholds in nerve injury models. Adapted from (Xie, Chew, et al. 2016) with permission.

4.4.2. ROS‐ and Redox‐ Responsive Release

ROS‐responsive NDDS are promising as a mechanism for targeted release in high‐inflammation pain microenvironments. Redox‐sensitive sulfide‐containing bonds are commonly used moieties (Tao and He 2018). For example, Quek et al. (2022) developed ibuprofen‐loaded polymeric micelles that release cargo in response to ROS by using a thioether‐containing block copolymer. In the presence of hydrogen peroxide (a model ROS), oxidation of the thioether group caused micelle disruption and allowed cargo release. In vitro experiments showed that ibuprofen was released in an induced inflammatory microenvironment, lowering expression of COX‐2 in LPS treated macrophages (Figure 5B) (Quek et al. 2022).

Disulfide and thioether bonds can be incorporated into MSNs, yielding ROS‐sensitive NDDS that disassemble in inflammatory environments. This technology was used by Xie et al. to co‐deliver d9‐THC and an anti‐inflammatory peptide Ara290. The complexes exhibited triggered release in vitro in response to ROS. The coloaded NDDS outperformed single‐drug NDDS, achieving nearly 28 days of analgesia in a chronic constriction injury model of neuropathic pain (Figure 5C) (Xie, Chew, et al. 2016). A similar technology was later used by Li et al. to enable delivery of an anti‐inflammatory neurotrophic factor selectively in inflamed colitis tissue (Li, Zhou, et al. 2025).

5. Translation Challenges and Research Gaps

Clinical translation of NDDS remains a major challenge in every subfield of nanomedicine. In the last section of this review, we highlight regulatory challenges specific to the field of pain, including preclinical characterization, manufacturing and clinical trial design, and then we identify areas with opportunities for innovation.

5.1. Regulatory Challenges

While the FDA has issued guidances on development of nanomaterials and for liposomal formulations, there does not yet exist a dedicated regulatory pathway for nanomaterials, thus NDDS are evaluated per‐case on existing small molecule and biologics framework (Drug Products, Including Biological Products, that Contain Nanomaterials—Guidance for Industry, 2022; Liposome Drug Products: Chemistry, Manufacturing, and Controls; Human Pharmacokinetics and Bioavailability; and Labeling Documentation, 2018). In depth analyses of nanomedicine regulatory strategies are discussed in other reviews; herein we highlight pain‐specific challenges (Rodríguez‐Gómez et al. 2025; Stucchi et al. 2026; Wang and Grainger 2022).

5.1.1. Preclinical Characterization

Current challenges in achieving chemistry, manufacturing, and characterization (CMC) regulatory benchmarks involve reproducibility and characterization of nanomaterials, and NDDS must adhere to Good Manufacturing Practices standards (Paliwal et al. 2014). For lipid‐ and polymer‐based formulations, shelf life, sterility, and batch variability are particular challenges—particularly since these NDDS are not suitable for terminal e‐beam sterilization, and often require cold chain storage (Kyriakidis et al. 2021). Drug release must be characterized using a validated protocol, which may complicate the progression of stimuli responsive NDDS for pain, in that novel release protocols must be developed and validated.

Safety and toxicity evaluations are of utmost importance in testing new nanomaterials, and evaluation of effects to the immune system, nervous system, and potential reproductive systems should be given attention in pain applications. For topical administration, which is relevant to pain, lymph node accumulation should be considered. The FDA assesses risk (in terms of safety and efficacy) for nanomaterials based on the complexity of the system, the predictability of the system compared to the free drug, and the degree of systemic exposure. If a formulation contains a novel nanocarrier component, it needs to have characterization data comparable to that of a new drug. Thus, there is a tradeoff in development between system complexity (which affords potentially more innovation and efficacy) and regulatory risk and workload.

Both pain and NDDS research have issues of animal model relevance. Despite their necessity for academic and preclinical research, and the wide use of standardized models for neuropathic pain, animal models fall short of capturing the complexity of human pain physiology (Clark 2016; Karimi et al. 2024). For NDDS, there is also increasing work showing species‐specific NDDS pharmacokinetics profiles, leading to difficulties in predicting and establishing in vitro–in vivo correlations (Lavé et al. 1999; Yuan et al. 2019). These issues have left a fragmented understanding of both pain and nanomedicine that limits translation. Among others, advances in in vitro human models, multi‐omics studies, and machine learning may help to bridge this gap.

5.1.2. Clinical Trial Design

Clinical trials of new pain management therapies have known and unique challenges. Patient recruitment, especially with chronic pain, is difficult due to the disabling effects of the condition and related socioeconomic burdens (Anastasi et al. 2024). Clinical endpoints are also difficult to measure due to the subjectivity of pain, and therefore both qualitative pain scores and quantitative biomarkers must be assessed. From a study design standpoint, the heterogeneity of pain pathophysiology across patients is a major issue, and the ethics of using a placebo control (which can often lead to unblinding) create complications. The placebo effect itself is known to be significant in pain management, with greater effect in chronic pain settings than acute, making actual therapeutic efficacy difficult to demonstrate (Kaptchuk et al. 2020).

To combat the heterogeneity of pain presentation, there is evidence that a personalized study design approach using N = 1, similar to the rare disease space, can be helpful in understanding the effects of treatment on a per‐patient basis (He et al. 2021). Another approach is to do a crossover trial, where each patient receives both active and control treatments. However, both these and N = 1 approaches require a treatment washout period, and they assume there is no temporal aspect to disease (and pain) progression, which is not the case for acute pain and may vary in chronic pain conditions (Dworkin et al. 2021). Specific pain pathologies should inform clinical trial design.

Clinical trials of NDDS also have unique challenges. Recommendations for NDDS specify a comparison between the nanoformulation and its free drug formulation (if possible) or another standard treatment—thus the heterogeneity of current treatment efficacy makes it difficult to demonstrate improvement. Additionally, for trial designs utilizing a washout period, the longer clearance rates of nanocarriers will need to be taken into consideration (Gabizon et al. 2003; Wang et al. 2013).

5.2. Research Gaps

5.2.1. Innovation in Scalable Processes and Manufacturing

Manufacturing and characterization of nanomaterials are an ongoing challenge in nanomedicine, with no exception for pain. This means that scaled production of a formulation must be considered from the onset of development (Ristroph 2024; Ristroph et al. 2025).

For polymer nanoparticles, continuous flow processes such as FNP have shown to be favorable for manufacturing at scale (Armstrong et al. 2023), but are limited in the types of drugs that can form stable NDDS (Pustulka et al. 2013). Sequential nanoprecipitation (SNaP) is an emergent process that shows promise for improving encapsulation of weakly hydrophobic drugs and slowing release rates while accessing new size regimes (Belinky et al. 2024; Lewis et al. 2025). A recent comparative study demonstrated improved drug loading and stability of ibuprofen nanoparticles synthesized via SNaP, suggesting that process innovation can expand the range of drugs amenable to nanoformulation—important given the wide variation in drug classes used in pain (El Amri et al. 2025).

Polydispersity of both size and drug loading of NDDS populations has been shown to impact the in vivo performance of the system, representing a major hurdle to improved vitro‐in vivo correlation (Peralta‐Cuevas et al. 2026). Significant differences in biodistribution, half‐life, and drug release rates exist within polymeric nanoparticle populations considered to be monodisperse (Jackman et al. 2024). Similarly, heterogenous payloads have been identified in clinically relevant liposomal formulations (Li, Hu, et al. 2024) Improved methods of identifying size and loading polydispersity, and development of robust and uniform nanoencapsulation methods, will be of critical importance to advance pain NDDS clinically.

The quality‐by‐design (QbD) approach can be a thoughtful approach for design of NDDS for pain with scale up and translation in mind (Girotra et al. 2016; Rawal et al. 2019). However, in order to integrate the QbD approach, a full understanding of the critical attributes of NDDS for pain, including nanocarrier behavior in pain microenvironments, is needed.

5.2.2. Delivery of Biologics and Gene Therapies

Biologics, including nucleic acids, peptides, proteins, and antibodies, are some of the most promising candidates for next‐generation pain therapy. However, effective strategies for encapsulation and effective delivery of biologics remain a large challenge in the field. In particular, biologics encapsulation offers protection from degradation and targeted, sustained delivery. Liposomes and lipid nanoparticles have demonstrated efficacy in delivering nucleic acids (Ickenstein and Garidel 2019), but there are limited strategies for encapsulating peptides, proteins, and antibodies, which make up a large fraction of efficacious anti‐pain biologics. Therapeutic peptides (enkephalins, conotoxins, etc.) are recognized as promising pain candidates due to their receptor selectivity and reduced side effect profiles, yet they remain clinically underutilized due to rapid enzymatic degradation and poor bioavailability. Developing reliable platforms that protect biologics from degradation while enabling targeted delivery to pain‐relevant tissues would unlock an entire class of therapeutics currently limited by pharmacokinetic barriers. Promising advances are emerging, particularly inverse FNP, which enables efficient encapsulation of biologics in polymeric nanoparticles, offering a scalable path toward clinical translation of biologic‐based pain therapies (Maiocchi et al. 2025; Markwalter et al. 2021).

Gene therapy is another promising technology for pain management (Li and Ji 2024). The biological machinery required for it inherently require encapsulation in a NDDS to enable entry in cell cytoplasm and protect from protease degradation (Zhen and Li 2020). In pain applications, it is important that gene modulation is epigenetic or semi‐permanent. Cell type specificity is also incredibly important. A major issue, however, is the sheer cost of gene therapies due to the difficulty in manufacturing—a cost that may be insurmountable given the burden of chronic pain (Wong et al. 2023). Shifting gene therapy platforms away from virus particles and toward the use of lipid and polymeric nanoparticle platforms may improve the cost and utility of these technologies in the long run (Sheridan 2023).

5.2.3. Advancing Responsive Platforms

Light‐controllable NDDSs offer molecular‐level strategic additions to NDDSs for on‐demand, localized pain control. However, one constraint is the limited tissue penetration depth of the working irradiation wavelength. Increasing irradiation intensity risks tissue damage by photothermal ablation at the target site (Smalley 2011). Development of light‐responsive materials with robust NIR sensitivity and sufficient photoconversion efficiencies to maximize light‐activated release and minimize irradiation time is crucial, as high‐frequency UV wavelengths cause DNA damage and have low penetration depth (Fomina et al. 2012). Various innovative NDDSs have been developed using the first NIR window (700–900 nm), but shifting into the second NIR region (900–1880 nm) would offer a higher maximum permissible exposure and reduced light scattering, resulting in enhanced drug delivery (Li et al. 2020; Zhang et al. 2024).

There are some avenues in responsive NDDS for pain that have not been reported in the literature. For one, the scope of externally‐triggered NDDSs remains mostly confined to local anesthetics and nerve block applications; extending this strategy to next‐generation pain therapeutics remains an unexplored opportunity. Additionally, enzyme‐triggered drug delivery systems have been utilized in cancer therapies, where overexpression of remodeling enzymes, such as matrix‐metalloproteases (MMP) leads to a distinct proteolytic microenvironment (Huang et al. 2019; Purcell et al. 2014). MMPs and other inflammatory enzymes are also associated with chronic pain, but this avenue has not yet been explored directly for pain applications of NDDS.

With regards to the potential clinical translation of stimuli‐responsive NDDS: current regulatory framework is not properly equipped to evaluate the complex and dynamic behavior of stimuli responsive nanoparticles. A handful of formulations in cancer and inflammation have progressed in phase I/II trials but have failed to meet efficacy endpoints. The mixed clinical success of ThermoDox, a thermoresponsive liposomal doxorubicin formulation, can be informative for potential pain applications. Among other issues, efficacy endpoints were not met due to variability in external trigger (local heating) execution (Dou et al. 2017). Thus, for externally triggered devices, the co‐design and standardization of a clinical trigger device is integral but may slow development (Bhairam et al. 2026; Regenold et al. 2022). Bridging data where possible, that is, in using validated nanocarriers (PLGA nanoparticles, liposomes, etc.), generally regarded as safe (GRAS) components, or unaltered approved therapeutic moieties, may help accelerate the development.

Responsive NDDS may eventually be clinically meaningful for patient‐ and disease‐informed treatment. However, as it is an emerging technology, further work on chemistry and material development is needed. Nevertheless, these systems can currently be used as powerful tools to understand drug delivery problems and inform solutions more thoroughly.

5.2.4. Biological Sex as a Variable

Women have a higher prevalence of chronic pain and report higher levels of disability due to pain (Lucas and Sohi 2023) While there may be psychosocial aspects, there are also undeniable biological foundations related to the immune system and sex hormones (Smith et al. 2025; Sorge and Totsch 2017). Animal models indicate differential involvement in immune cell recruitment and contribution to chronic pain, with males having a higher contribution of microglia cells and females having a higher contribution of T‐cells (Sorge et al. 2015). Consequently, pain interventions have differences in efficacy based on sex; for example, CLR antagonists are more effective in treating migraine in females than in males, possibly due to higher expression of local CGRP (Kuzawińska et al. 2014; Porreca et al. 2024).

The delivery challenges arising from sex‐based differences in pain pathophysiology may be confounded by known sex‐based differences in NDDS pharmacokinetics (Hajipour et al. 2021). Males exhibit greater liver accumulation of nanoparticles, and females exhibit greater kidney accumulation and slower clearance rates (Poley, Chen, et al. 2022; Toita et al. 2026). Additionally, evidence of 2‐fold increase in nanoparticle accumulation in reproductive organs of mice during ovulation indicates hormone‐dependent biodistribution patterns (Poley, Mora‐Raimundo, et al. 2022). While some of these differences may create interesting opportunities for pain NDDS, such as the potential for endometriosis lesion targeting, it underscores the difficulty with developing a generalized anti‐pain nanoformulation. At minimum, pain NDDS researchers should consider biological sex as a variable in preclinical and clinical investigations, and ensure that the populations that stand to benefit the most from their work are adequately represented.

5.2.5. Understanding Nano‐Bio Interactions in Pain

The field of nanomedicine has made substantial progress in understanding how nanoparticles interact with biological systems. However, most of this knowledge derives from cancer nanomedicine and research has focused on tumor, hepatic, renal, and immune system interactions. Pain nanomedicine requires understanding interactions with a fundamentally different set of biological actors: sensory neurons, immune cells, and the specialized microenvironments of peripheral nerve terminals and the spinal cord. This knowledge gap represents the primary barrier preventing pain NDDS from evolving beyond improved PK profiles of existing drugs toward designs that exploit pain‐specific biology. Many critical questions remain unanswered: How do nanoparticle properties influence uptake at nerve terminals versus neuronal cell bodies, and how are they trafficked in sensory neurons? Do nanoparticles alter neuronal excitability or neurotransmitter release? Does the altered microenvironment of injured nerves (changed pH, ROS, proteases, blood‐nerve barrier permeability, and neuro‐immune crosstalk) affect NDDS behavior in exploitable ways?

Addressing this gap requires in vitro models recapitulating pain biology: in vitro models, including microfluidic systems enabling separate access to cell bodies and terminals (Dante et al. 2017; Lesniak et al. 2019), advanced imaging techniques such as intravital microscopy, two‐photon imaging, and correlative microscopy, systematic structure–activity studies, and interdisciplinary collaboration between materials scientists, neuroscientists, and clinicians. Until we develop this foundational understanding, pain NDDS will remain limited to incremental pharmacokinetic improvements rather than transformative strategies exploiting pain‐specific biology. This represents the field's greatest opportunity and most pressing challenge.

6. Conclusions and Outlook

Pain is a challenging healthcare issue that will continue to limit quality of life for a significant portion of the population until transformative therapies become available. The opioid epidemic has starkly demonstrated the consequences of relying on addictive analgesics with severe side effects, making innovation in pain management critical for public health. Nanomedicine represents a viable approach for developing improved pain therapies that address fundamental limitations such as low bioavailability, high clearance rates, and off‐target effects, while offering potential for non‐addictive alternatives that reduce rather than worsen the opioid crisis. Multimodal and rationally designed NDDS have made progress in both well‐defined and emerging preclinical models and a handful of formulations have made progress clinically. Substantial biological, chemical, and material hurdles remain for clinical translation.

Improved characterization and control over nanomaterial properties are needed and remain a challenge in nanomedicine. In the field of pain, we need a better understanding of how nanomaterials interact with the major biological actors of pain, and how the heterogeneity of pain presentation impacts nanomedicine efficacy. Spatiotemporal control of drug action, critical for achieving platforms that are useful throughout the diverse pain physiological landscape, must be judiciously integrated through targeting the pain microenvironment or subcellular targets, or external control through stimuli‐sensitive platforms. Critically, pain nanomedicines must avoid perpetuating addiction; therefore, a movement away from the opioid landscape is necessary.

Looking ahead, translating pain‐focused NDDS will require innovations in in vitro and in vivo models of pain to effectively test new technologies and advance through regulatory pathways. Improvements in scalable manufacturing are needed to ensure reliable drug loading and biodistribution. Our best guidelines: rational design of NDDS that transform candidates into precise therapies tailored to specific pain physiological states, keeping good faith efforts to mind translation and manufacturing goals from the onset of development.

Author Contributions

Rachel E. Pollard: data curation, supervision, writing – original draft, writing – review and editing, conceptualization. Amy S. Moreno: data curation, writing – original draft, writing – review and editing. Vic M. Hempstead: data curation, writing – original draft, writing – review and editing. Alan D. Hegron: data curation, writing – original draft. Parker K. Lewis: data curation. Kiana Bahrami: data curation. Badr Sokrat: data curation. Brian L. Schmidt: conceptualization, funding acquisition, writing – review and editing, supervision. Nigel W. Bunnett: conceptualization, supervision, writing – review and editing, funding acquisition. Dane D. Jensen: conceptualization, writing – review and editing, supervision. Nathalie M. Pinkerton: conceptualization, writing – original draft, writing – review and editing, funding acquisition, supervision.

Funding

This work was supported by grants from the National Institutes of Health (NS102722, DE026806, DK118971, DE029951, RM1DE033491).

Conflicts of Interest

Nathalie M. Pinkerton reports a consulting or advisory relationship with Endosome Therapeutics. Nigel W. Bunnett reports an equity or stock ownership interest in Endosome Therapeutics. All other authors declare that they have no known competing financial interests or personal relationships that could have influenced the work reported in this paper.

Pollard, R. E. , Moreno A. S., Hempstead V. M., et al. 2026. “Engineering Nanoscale Drug Delivery Systems for Pain.” Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology 18, no. 4: e70072. 10.1002/wnan.70072.

Data Availability Statement

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.