I.

INTRODUCTION
Conventional sustained and controlled release formulations have improved therapy by stabilizing
plasma drug levels and reducing dosing frequency compared with immediate-release products. These
systems, based mainly on matrix, reservoir, osmotic or coating technologies, were designed to control
the temporal profile of drug input but remain largely passive and population-oriented. Increasing
disease complexity, the rise of biologics and nucleic acid therapies, and the move toward precision
medicine have highlighted important limitations of such approaches and motivated the development
of next-generation drug delivery strategies.
Next-generation systems aim to combine prolonged action with spatial targeting,
stimuli-responsiveness and, increasingly, integration with diagnostic and digital technologies
[2,3,6,10–12,16]. They exploit advances in materials science, nanotechnology and biotechnology to
address biological barriers more effectively and to better align dosing with dynamic pathophysiology
and individual patient needs [1–3,6,10,18–20].
A. Evolution of Drug Delivery Systems
Drug therapy initially relied on immediate-release dosage forms, where outcomes depended on dosing
frequency, adherence and intrinsic pharmacokinetics. Sustained and controlled release systems
represented a major step forward by extending release, smoothing concentration–time profiles and
improving convenience. As polymer and colloidal technologies matured, research shifted from simple
time-control toward improving solubility, stability and tissue distribution, creating the basis for
targeted and responsive delivery paradigms [2–4,10,13,18].
B. Limitations of Conventional Sustained and Controlled Release
Classical sustained and controlled release formulations are usually designed for average physiology
and lack mechanisms to adapt to inter- and intra-patient variability, making performance less
predictable in special populations [1–3,5,19]. They also provide limited spatial control, exposing
healthy tissues to drug and reducing therapeutic indices, especially for narrow-therapeutic-index
agents [1–3,7–9,15]. Many are poorly suited for fragile macromolecules and cannot respond to
dynamic biomarkers or integrate with monitoring tools, underscoring the need for more adaptable and
intelligent systems.
C. Need for Next-Generation Drug Delivery Strategies
Next-generation systems seek integrated control over “when”, “where” and “to whom” a drug is
delivered. They include platforms that respond to endogenous stimuli such as pH, enzymes or redox
gradients, or to external triggers such as light, magnetic fields or ultrasound, enabling
context-dependent or on-demand release. In parallel, passive and active targeting, biomimetic carriers
and organ-specific approaches aim to enhance spatial precision and reduce systemic toxicity [2,3,7–
9,11,15]. Increasingly, these technologies interface with sensors, wearable or implantable devices and
digital tools, making closed-loop, data-driven therapy a realistic prospect [10–12,16,20].
D. Scope and Objectives of the Review
This review provides an overview of drug delivery strategies that move beyond conventional
sustained and controlled release. It (i) summarizes fundamental pharmacokinetic, pharmacodynamic
and biological aspects relevant to advanced systems; (ii) analyzes limitations of traditional platforms;
and (iii) describes emerging paradigms such as precision/personalized delivery, smart and
stimuli-responsive systems, and nano-biointegration [1–6,10,13,18,19]. It further (iv) surveys key
platforms (nanocarriers, dendrimers, micelles, hydrogels, biomimetic and exosome-based systems),
(v) discusses targeted delivery, gene and nucleic acid delivery, novel routes and device-enabled
technologies, and (vi) considers roles of artificial intelligence, safety, toxicity and regulation,
concluding with future opportunities [2,3,6,7,10–12,14,16,18–20].

II. FUNDAMENTALS OF DRUG DELIVERY

A. Pharmacokinetic and Pharmacodynamic Considerations
Rational design of advanced drug delivery systems requires alignment of formulation performance
with pharmacokinetic (PK) and pharmacodynamic (PD) requirements [1,3]. PK parameters such as
clearance, half-life and volume of distribution determine the systemic exposure that a delivery system
must achieve or modify, while PD relationships define how concentration translates into therapeutic
and toxic responses. Conventional sustained release formulations primarily smooth plasma profiles,
but next-generation systems increasingly aim to match complex PD targets, such as pulsatile or
circadian patterns and narrow therapeutic windows. For biologics and high-risk drugs, small
deviations in exposure can markedly affect efficacy and safety, making precise control of Cmax, AUC
and local tissue levels a critical driver for more sophisticated delivery concepts.
B. Biological Barriers to Drug Delivery
Drug delivery systems must overcome multiple biological barriers before reaching their targets,
including epithelial and endothelial tight junctions, mucus layers, enzymatic degradation, immune
recognition and clearance, and organ-specific microenvironments [1–3]. For oral administration,
variable pH, digestive enzymes and efflux transporters in the gastrointestinal tract can severely limit
bioavailability, particularly of labile or poorly soluble drugs. Systemically administered carriers face
opsonization, phagocytic uptake and renal filtration, all of which can reduce circulation time and alter
biodistribution [1–3,10,11]. Next-generation platforms address these barriers through tailored size and
surface properties, stealth coatings, mucoadhesive or mucus-penetrating materials and exploitation of
receptor-mediated transport pathways, thereby improving the likelihood of reaching intended sites of
action [2,3,6,10–12,18].
C. Drug Physicochemical Properties and Their Impact
The physicochemical characteristics of a drug strongly influence feasible delivery strategies. Key
parameters include solubility, lipophilicity, ionization, molecular weight and chemical or enzymatic
stability [1–3,4]. Classical sustained release systems are generally better suited to small, relatively
stable molecules, whereas many next-generation platforms are specifically designed for poorly
soluble compounds, peptides, proteins and nucleic acids. Nanocarriers, for example, can enhance
apparent solubility and permeability of Biopharmaceutics Classification System (BCS) class II and IV
drugs, while encapsulation or conjugation strategies can protect labile molecules from degradation
and improve their pharmacokinetic profiles [2–4,10,18]. Therefore, understanding drug–excipient
interactions, solid-state properties and degradation pathways is essential when selecting or
engineering advanced systems, and carrier composition and architecture must be tailored to the
specific physicochemical profile of the active molecule [2–4,10,18,19].
III. LIMITATIONS OF CONVENTIONAL DRUG DELIVERY SYSTEMS
Conventional sustained and controlled release systems improve therapy but exhibit important
limitations that restrict their suitability for many modern drugs and treatment paradigms [1–
3,5,18,19]. Key issues include formulation-dependent variability, risk of dose dumping, limited spatial
targeting, variable absorption and bioavailability, and persistent challenges with patient adherence in
real-world use [1–3,5,18,19].
A. Challenges in Sustained and Controlled Release
Designing robust sustained and controlled release formulations is difficult due to the need to balance
drug properties, excipient functionality and physiological variability. Many systems are sensitive to
changes in gastrointestinal pH, motility or fluid volume, which can alter release kinetics and
compromise the intended profile, particularly for orally administered dosage forms. Complex
manufacturing, stringent quality control requirements and difficulties in establishing in vitro–in vivo
correlations further complicate development and [Link]+5
B. Dose Dumping and Poor Targeting
Because sustained and controlled release products typically contain a relatively large drug load,
failure of the release-controlling mechanism can lead to dose dumping and acute toxicity, especially
for potent or narrow-therapeutic-index drugs [1–3,5,18]. Factors such as alcohol co-ingestion,
mechanical damage, formulation defects or unexpected physiological conditions may accelerate drug
release and destabilize plasma concentrations [1–3,18]. Moreover, most conventional systems mainly
act by modifying release rate rather than biodistribution, offering little intrinsic spatial selectivity and
thus exposing healthy tissues to unnecessary drug levels [2,3,7–9,15].
C. Variability in Drug Absorption and Bioavailability
Sustained and controlled release formulations are typically designed using average physiological
parameters, yet gastrointestinal transit times, pH, enzyme activity and transporter expression show
substantial inter- and intra-patient variability [1–3,19]. As a result, absorption and bioavailability may
vary markedly between individuals and even within the same patient over time, which is particularly
problematic for drugs with narrow therapeutic indices. Additional sources of variability include food
effects, comorbidities, concomitant medications and age-related physiological changes, all of which
are difficult to fully accommodate in conventional designs [1–3,5,19].
D. Patient Compliance Issues
While reduced dosing frequency is intended to enhance adherence, sustained and controlled release
products can pose their own compliance challenges. Many oral modified-release tablets or capsules
are relatively large, must not be crushed or chewed and often come with strict administration
instructions, which can be problematic for pediatric, geriatric and dysphagic patients. In addition,
delayed onset of action and limited flexibility for rapid dose adjustment may reduce patient
satisfaction and complicate individualized therapy, especially in conditions requiring titration or rapid
symptom control. Together, these limitations motivate the development of next-generation systems
that combine controlled release with improved safety, targeting and patient-centric designed.
IV. EMERGING PARADIGMS IN NEXT-GENERATION DRUG DELIVERY
Next-generation drug delivery strategies aim to address the temporal, spatial and patient-specific
limitations of conventional sustained and controlled release systems by integrating precision,
responsiveness and advanced materials or biological tools. These paradigms increasingly align
formulation design with the principles of precision medicine, real-time physiological responsiveness
and rational exploitation of nano- and biotechnologies [2,3,6,10–12,16].
A. Concept of Precision and Personalized Drug Delivery
Precision and personalized drug delivery seek to tailor not only the drug and dose but also the delivery
system and release profile to individual patient characteristics, including genetics, disease phenotype,
organ function and comorbidities. In this paradigm, formulation design is informed by
pharmacogenomic data, biomarker profiles and disease staging, enabling selection or customization of
systems that deliver the right amount of drug to the right site at the right time for a specific patient.
Such approaches also emphasize patient-centric attributes—such as dosage form preference, ability to
self-administer and lifestyle factors—to improve adherence and real-world effectiveness. Ultimately,
precision delivery provides a conceptual bridge between classical controlled release technologies and
more sophisticated platforms capable of supporting individualized therapy.
B. Smart and Stimuli-Responsive Systems
Smart and stimuli-responsive delivery systems are designed to alter their behaviour in response to
specific internal or external cues, thereby providing context-dependent or on-demand drug release.
Endogenous stimuli exploited include pH differences between healthy and diseased tissues, redox
gradients, enzyme overexpression, hypoxia and metabolite levels such as glucose, while exogenous
stimuli include light, magnetic fields, ultrasound and electrical signals. By coupling drug release to
such triggers, these systems can more closely match dosing to dynamic disease activity, potentially
improving therapeutic indices and reducing off-target effects compared with passive sustained release
formulations. Emerging platforms combine multiple triggers or incorporate feedback elements,
positioning smart systems as core components of future closed-loop or self-regulated therapies [10–
12,16,20].
C. Integration of Nanotechnology and Biotechnology
The integration of nanotechnology and biotechnology has profoundly expanded the design space for
advanced drug delivery systems [2–4,6,10,13,18]. Nanoscale carriers—including liposomes,
polymeric nanoparticles, solid lipid nanoparticles, dendrimers and micelles—offer tunable size,
surface properties and loading capacity, enabling improved solubility, protection and controlled
release of diverse therapeutic cargoes [2–4,10,18]. Biotechnology contributes targeting ligands,
antibodies, peptides and other biomolecules, as well as biomimetic and cell-derived components that
can enhance specificity, circulation time and barrier penetration [2,3,6,7–9,11,15,18]. Together, these
technologies support platforms capable of combining prolonged action, active targeting,
stimuli-responsiveness and diagnostic or imaging functions within a single system, thereby laying the
foundation for theranostic and multifunctional next-generation drug delivery strategies that will be
discussed in subsequent sections.
V. ADVANCED DRUG DELIVERY PLATFORMS
Advanced platforms operationalize the paradigms outlined in Section 4 by providing concrete
technological solutions for improved control over drug release, targeting and responsiveness [2–
4,6,10,13,18]. Key classes include nanocarriers, dendrimers and micelles, hydrogels and injectable
depots, biomimetic and cell-based systems, and exosomes or other extracellular vesicles, each with
distinct strengths and limitations [2–4,6,10,18].
A. Nanocarriers (Liposomes, Polymeric Nanoparticles, Solid Lipid Nanoparticles)
Nanocarriers are sub-micron delivery systems designed to encapsulate or associate drugs and
modulate their solubility, stability, biodistribution and release profile [2–4,10,18]. Liposomes and
lipid nanoparticles can accommodate both hydrophilic and hydrophobic agents and have achieved
multiple clinical approvals, particularly in oncology and more recently for nucleic acid delivery [2–
4,10,11,18]. Polymeric nanoparticles offer versatile architectures and surface functionalization options
for controlled and targeted delivery, while solid lipid nanoparticles and nanostructured lipid carriers
combine the biocompatibility of lipids with improved physical stability and scalability [2–4,10,18,19].
Collectively, these systems represent core building blocks for next-generation formulations, including
stimuli-responsive and targeted nanomedicines.
B. Dendrimers and Micelles
Dendrimers are highly branched, monodisperse macromolecules with interior cavities and abundant
surface groups, enabling high drug loading via encapsulation or conjugation and precise control over
size and surface chemistry [2–4,6,10,18]. Their multivalent surfaces can be engineered with targeting
ligands or stimuli-responsive linkers, supporting both controlled release and site-specific delivery [2–
4,6,10]. Polymeric micelles, formed by self-assembly of amphiphilic block copolymers, provide
hydrophobic cores for solubilizing poorly soluble drugs and hydrophilic coronas for improved
circulation and reduced opsonization [2–4,6,10,18]. Both dendrimers and micelles are particularly
attractive for delivering hydrophobic small molecules and, with appropriate functionalization, can be
integrated into targeted and stimuli-responsive designs.
C. Hydrogels and Injectable Systems
Hydrogels are hydrophilic polymer networks capable of absorbing large amounts of water and hosting
drugs or biologics in a three-dimensional matrix, enabling sustained or stimuli-responsive release [2–
4,10,18]. Injectable hydrogels, including in situ-forming systems, can be administered minimally
invasively and subsequently gel at the target site, providing localized depots for controlled delivery
[2–4,10,18,19]. Their mechanical and degradation properties can be tuned to match specific tissues,
and they can be combined with cells, nanoparticles or bioactive molecules, making them attractive for
regenerative medicine and localized chemotherapy [2–4,10,18]. These features position hydrogels as
versatile platforms that bridge classical controlled release with emerging tissue-engineered and
combination products.
D. Biomimetic and Cell-Based Delivery Systems
Biomimetic and cell-based systems aim to exploit or emulate endogenous structures and processes to
improve circulation, targeting and biocompatibility [2,3,6,7–9,11,15,18]. Examples include red blood
cell-, platelet- or leukocyte-mimicking particles, cell membrane-coated nanoparticles and live or
modified cells used as carriers for drugs, genes or oncolytic agents [2,3,7–9,11,15]. By presenting
natural surface markers and interfaces, such systems can evade immune clearance, home to specific
tissues or inflammatory sites and interact with disease-relevant microenvironments more effectively
than purely synthetic carriers [2,3,7–9,11,15,18]. However, they also raise additional challenges
related to reproducibility, manufacturing, storage and regulatory evaluation.
E. Exosomes and Extracellular Vesicles
Exosomes and other extracellular vesicles (EVs) are nanoscale membrane vesicles released by cells
that naturally mediate intercellular communication and can carry proteins, lipids and nucleic acids.
Their intrinsic biocompatibility, ability to cross certain biological barriers and potential for selective
tissue tropism make them promising candidates for next-generation drug and gene delivery vehicles.
Engineered exosomes can be loaded with therapeutic cargo and modified to enhance targeting or
control release, and they are increasingly explored in oncology, neurology and regenerative medicine.
Nonetheless, standardization of isolation, characterization, loading and large-scale production remains
a major barrier to clinical translation, highlighting the need for harmonized methodologies and
regulatory frameworks.

VI. TARGETED DRUG DELIVERY APPROACHES

Targeted drug delivery approaches aim to concentrate therapeutic agents at specific tissues or cells
while minimizing systemic exposure, thereby improving efficacy and reducing toxicity relative to
non-targeted sustained and controlled release systems [2,3,7–9,11,15]. Two major paradigms are
passive targeting, which exploits pathophysiological features such as the enhanced permeability and
retention (EPR) effect, and active targeting, which relies on ligand–receptor interactions; both are
complemented by organ-specific and blood–brain barrier (BBB)-focused strategies [2,3,7–
9,11,15,18].
A. Passive Targeting (EPR Effect)
Passive targeting refers to the preferential accumulation of macromolecules and nanoparticles in
pathological tissues, most notably solid tumours, due to leaky vasculature and impaired lymphatic
drainage—a phenomenon known as the EPR effect [2,3,7–9,11,15,18]. Numerous preclinical studies
demonstrate increased tumour uptake of nanocarriers via EPR, and several clinically approved
nanomedicines leverage this mechanism to enhance intratumoural drug concentrations compared with
conventional formulations [2,3,7–9,11,15,18]. However, the magnitude and consistency of the EPR
effect vary substantially between tumour types, patients and anatomical sites, and may be limited in
certain indications, emphasizing the need for complementary active and
microenvironment-modulating strategies [2,3,7–9,11,15,18].
B. Active Targeting (Ligand–Receptor Mediated)
Active targeting involves functionalizing drug carriers with ligands—such as antibodies, peptides,
aptamers or small molecules—that recognize and bind specific receptors or markers overexpressed on
target cells or tissues [2,3,7–9,11,15,18]. Following ligand binding, carriers can undergo
receptor-mediated endocytosis or preferential retention at the disease site, potentially increasing local
drug concentration and improving therapeutic indices without necessarily changing overall
biodistribution dramatically [2,3,7–9,11,15]. Successful active targeting requires careful optimization
of ligand density, affinity, orientation and carrier physicochemical properties, as well as consideration
of target receptor expression heterogeneity and potential off-target binding [2,3,7–9,11,15,18].
C. Organ-Specific and Cellular Targeting
Organ-specific and cellular targeting strategies extend passive and active concepts to direct
therapeutics to particular organs, tissues or cell types beyond solid tumours [2,3,7–9,11,15,18]. These
approaches include exploiting organ-specific vascular features, using ligands for receptors enriched in
certain tissues (e.g. liver, lung or inflamed endothelium), or designing carriers that preferentially
interact with immune cells, stem cells or other relevant populations [2,3,7–9,11,15]. Biomimetic
carriers, including cell membrane-coated nanoparticles and cell-based systems, further enhance
specificity by reproducing native homing and adhesion processes, thereby improving targeting to sites
of inflammation, injury or metastasis [2,3,7–9,11,15,18]. Such strategies support the development of
more precise therapies, particularly in oncology, inflammatory diseases and regenerative medicine.
D. Blood–Brain Barrier Targeting Strategies
The BBB presents a major obstacle to delivering many therapeutics to the central nervous system,
necessitating specialized targeting strategies. Approaches include transient modulation or disruption
of the BBB using physical methods (e.g. focused ultrasound with microbubbles), exploitation of
endogenous transport mechanisms such as receptor- or carrier-mediated transcytosis, and design of
nanoparticles or biomimetic systems capable of crossing or bypassing the barrier. Ligands that bind
receptors expressed at the BBB (e.g. transferrin or insulin receptors), cell-penetrating peptides and
exosome-based carriers have all been investigated to enhance brain uptake of small molecules,
peptides, proteins and nucleic acids. These strategies exemplify how targeted delivery concepts must
be adapted to specific anatomical and physiological barriers and will be increasingly relevant for
treating neurological and neurodegenerative diseases.

VII. STIMULI-RESPONSIVE AND SMART DRUG DELIVERY SYSTEMS

Stimuli-responsive and smart drug delivery systems are designed to alter their behaviour in response
to specific internal or external cues, thereby enabling controlled, localized or on-demand release that
is not achievable with conventional sustained and controlled release formulations. These platforms
 frequently combine responsive materials with nanoscale or device-based carriers and are central to
efforts to develop closed-loop and highly adaptive therapies [3,5,6,10–12,16,20].
A. pH-Responsive Systems
pH-responsive systems exploit pH differences between physiological compartments or between
healthy and diseased tissues, such as the mildly acidic tumour microenvironment or
endosomal/lysosomal compartments. Carriers are typically constructed from polymers or linkages that
undergo ionization, conformational change or bond cleavage at defined pH values, triggering drug
release at the target site while limiting release in circulation or healthy tissues. These systems have
been widely investigated for cancer therapy and for oral delivery of acid-labile or site-specific drugs,
where they can reduce systemic toxicity and improve local drug exposure compared with
non-responsive sustained release formulations.
B. Temperature-Sensitive Systems
Temperature-sensitive systems respond to changes in temperature by undergoing phase transitions,
gel–sol transformations or alterations in permeability, which can be used to control drug release.
Many designs exploit polymers with lower or upper critical solution temperatures near physiological
values, enabling injectable formulations that form gels in situ or carriers that release cargo when
exposed to locally elevated temperatures induced by external heating or hyperthermia. Such systems
have been explored for localized cancer therapy and tissue engineering, where mild hyperthermia or
disease-associated temperature changes can be harnessed to enhance spatial and temporal control of
drug delivery.
C. Enzyme-Responsive Delivery
Enzyme-responsive systems are designed to exploit differences in enzyme expression or activity
between healthy and diseased tissues, such as overexpressed proteases, glycosidases or phosphatases
in tumours, inflamed tissues or fibrotic lesions. These platforms often incorporate peptide or polymer
linkers that are selectively cleaved by target enzymes, or matrices whose degradation is accelerated in
enzyme-rich environments, thereby enabling site-specific or microenvironment-dependent drug
release. By coupling drug liberation to enzymatic activity, such systems can increase local drug
concentrations at pathological sites while minimizing exposure in off-target tissues, and they are
particularly attractive for cancer, inflammatory and cardiovascular indications.
D. Light, Magnetic, and Ultrasound-Triggered Systems
Externally triggered systems use physical stimuli such as light, magnetic fields or ultrasound to
initiate or modulate drug release at a chosen time and location. Light-responsive carriers may contain
photo-cleavable linkers or photosensitive components that release drug upon irradiation, whereas
magnetic-responsive systems typically rely on magnetic nanoparticles that generate heat or
mechanical forces under alternating magnetic fields, leading to triggered release or enhanced
accumulation. Ultrasound-responsive formulations—such as microbubbles, nanobubbles, liposomes
or hydrogels—can be disrupted or permeabilized by focused ultrasound, enabling non-invasive spatial
control and, in some cases, simultaneous imaging and therapy (theranostics). Together, these
externally controlled systems offer flexible, operator-directed modulation of drug delivery and are
promising for precision interventions in oncology, cardiovascular disease and other localized
pathologies.
VIII. GENE AND NUCLEIC ACID DELIVERY SYSTEMS
Gene and nucleic acid therapies, including siRNA, mRNA and CRISPR-based approaches, require
delivery systems capable of protecting labile cargo, enabling cellular uptake, promoting appropriate
intracellular trafficking and, in some cases, supporting nuclear entry. Both viral and non-viral vectors
have been developed to meet these demands, each with distinct advantages and limitations that shape
their suitability for next-generation drug delivery strategies.
A. siRNA, mRNA, and CRISPR-Based Delivery
Short interfering RNA (siRNA), messenger RNA (mRNA) and CRISPR/Cas systems enable
post-transcriptional gene silencing, transient protein expression and precise genome editing,
respectively, but all suffer from instability, large size and polyanionic character that preclude efficient
naked delivery. Lipid-based nanoparticles, polymeric carriers and certain viral vectors have therefore
been developed to encapsulate or complex these nucleic acids, shield them from nucleases and
facilitate cellular uptake and endosomal escape. Clinically, lipid nanoparticles for mRNA and siRNA
delivery have already been approved or advanced into late-stage trials, and an increasing number of
formulations are being evaluated for in vivo CRISPR delivery, underscoring the translational potential
of appropriately engineered systems.
B. Viral vs Non-Viral Vectors
Viral vectors such as adeno-associated viruses, adenoviruses and lentiviruses provide efficient gene
transfer and sustained expression, and have underpinned many early successes in gene therapy.
However, issues including limited cargo capacity, immunogenicity, insertional mutagenesis risk,
manufacturing complexity and high cost constrain their broader application and motivate the search
for alternatives. Non-viral vectors based on lipids, polymers, inorganic nanoparticles and hybrid
systems offer greater design flexibility, lower immunogenicity and fewer safety concerns, although
their transfection efficiency and in vivo performance have historically lagged behind viral systems.
Recent advances in nanotechnology, surface engineering and stimuli-responsive materials are closing
this gap, positioning non-viral vectors as key components of next-generation gene and nucleic acid
delivery platforms.
C. Challenges in Gene Delivery
Despite substantial progress, gene and nucleic acid delivery remains limited by multiple extracellular
and intracellular barriers, including serum instability, opsonization and clearance, inefficient tissue
and cellular targeting, endosomal trapping and suboptimal nuclear or cytosolic trafficking. Safety
concerns, particularly off-target effects, uncontrolled immune activation and long-term genomic
consequences for genome-editing systems, necessitate finely tuned vector design and rigorous
preclinical evaluation. In parallel, scalable manufacturing, reproducible characterization, regulatory
standardization and cost-effective deployment pose significant translational challenges, especially for
complex, multifunctional or personalized formulations. Addressing these issues is essential for
integrating gene and nucleic acid delivery into the broader landscape of next-generation drug delivery
described in this review.
IX. NOVEL DRUG DELIVERY ROUTES AND TECHNOLOGIES
Novel administration routes and device-enabled technologies seek to overcome limitations of
conventional oral and parenteral delivery by improving patient convenience, targeting and control
over drug input [2–4,10,11,18]. Key areas include advanced transdermal and microneedle systems,
pulmonary and nasal delivery, oral delivery of biologics, and implantable or wearable devices for
programmable or responsive dosing [2–4,10,11,18].
A. Transdermal and Microneedle Systems
Transdermal systems offer non-invasive, sustained delivery while bypassing first-pass metabolism,
but traditional patches are limited to drugs with suitable potency and physicochemical properties due
to the barrier function of the stratum corneum [2–4,10,18]. Microneedle technologies—using
micron-scale needles in solid, coated, dissolving or hydrogel-forming formats—create transient
microchannels in the skin, enabling delivery of a broader range of molecules, including vaccines and
biologics, with minimal pain and high patient acceptability [2–4,10,18]. Recent developments also
integrate sensors, electrical stimulation or other functionalities with microneedles, linking transdermal
delivery to real-time monitoring and intelligent control [2–4,10,11,18].
B. Pulmonary and Nasal Delivery
Pulmonary and nasal routes provide direct access to the respiratory tract and, in some cases, the
systemic circulation, enabling rapid onset of action and dose reduction compared with oral or
injectable routes [2–4,10,18]. Advances in particle engineering, inhaler design and nanocarrier-based
aerosols have improved deposition, mucosal penetration and retention in the lung, supporting targeted
treatment of respiratory diseases and systemic delivery of small molecules and biologics [2–4,10,18].
Nasal delivery is also being explored for brain targeting via nose-to-brain pathways and for
nasopulmonary systems that exploit the rich vascularization and large surface area of the nasal cavity,
although challenges such as mucociliary clearance and formulation stability remain [2–4,10,18].
C. Oral Delivery of Biologics
Oral delivery of biologics remains highly attractive from a patient perspective but is hindered by harsh
gastrointestinal conditions, enzymatic degradation and poor permeability across the intestinal
epithelium [2–4,10,18]. Strategies under investigation include permeation enhancers, protease
inhibitors, mucoadhesive and mucus-penetrating systems, pH-responsive and targeted nanoparticles,
and ingestible devices capable of injecting or releasing biologics directly into the intestinal wall [2–
4,10,18]. Although clinical translation has been limited to date, increasing understanding of
gastrointestinal physiology and advances in materials and device engineering are narrowing the gap
between experimental success and practical oral biologic products [2–4,10,11,18].
D. Implantable and Wearable Drug Delivery Devices
Implantable and wearable devices provide programmable, often minimally invasive platforms for
long-term or on-demand drug administration, aligning closely with the goals of precision and
patient-centric therapy [2–4,10,11,14,18]. Implantable systems include depots, pumps and
microfabricated devices that can deliver drugs over months or years, sometimes with externally
controlled or stimuli-responsive release, while wearable technologies encompass infusion pumps,
smart pens, on-body injectors and integrated inhaler or patch systems [2–4,10,11,14,18]. Coupled with
sensors, connectivity and data analytics, these platforms enable real-time monitoring, dose adjustment
and integration into digital health ecosystems, but raise additional challenges related to device
reliability, user interface, cybersecurity and regulatory evaluation as combination products [2–
4,10,11,14,18].
X. ROLE OF ARTIFICIAL INTELLIGENCE AND DIGITAL TECHNOLOGIES
Artificial intelligence (AI), predictive modeling and digital health technologies are increasingly
integrated into drug delivery research and practice, supporting rational design of delivery systems,
optimization of clinical use and real-time monitoring of therapy [10–12,16,18–20]. These tools span
in silico formulation design, connected drug delivery devices and multi-scale simulations of drug
transport and performance [10–12,16,18–20].
A. AI in Drug Delivery Design and Optimization
AI and machine learning (ML) approaches are being applied to predict relationships between
formulation variables, material properties and performance metrics such as release profiles, stability,
biodistribution and targeting efficiency, thereby accelerating development and reducing experimental
burden [10–12,16,18–20]. Data-driven models have been developed to support the design and
optimization of nanoparticle-based systems, selection of excipients and process parameters, and
prediction of pharmacokinetic behaviour, often outperforming traditional one-factor-at-a-time or
purely mechanistic approaches [10–12,16,18–20]. In parallel, AI-enabled personalization uses
patient-specific data to inform dosing strategies and may eventually guide selection of delivery
platforms best suited to individual needs [10–12,16,18–20].
B. Digital Health Integration and Smart Devices
Digital health technologies, including connected drug delivery devices and platforms, enable
integration of dosing, physiological monitoring and behavioural data, supporting more precise and
patient-centric therapy [10–12,16,18–20]. Smart injectors, inhalers, pens and wearable pumps
equipped with sensors and connectivity can record dosing events, measure adherence and, in some
cases, capture physiological signals that inform therapy adjustments [10–12,16,18–20]. When
integrated into broader digital health ecosystems, these devices facilitate remote monitoring, clinician
feedback and data-driven interventions, but they also require robust cybersecurity, interoperability and
regulatory frameworks as software- and device-inclusive combination products [10–12,16,18–20].
C. Predictive Modeling and Simulation
Predictive modeling and simulation, including multi-scale and AI-enhanced approaches, are becoming
indispensable tools for understanding and optimizing drug transport, delivery system performance and
clinical outcomes [10–12,16,18–20]. Mechanistic and hybrid models can integrate processes across
molecular, cellular, tissue and whole-body scales to predict phenomena such as nanoparticle
distribution, depot erosion, tissue penetration and therapeutic response under various conditions [10–
12,16,18–20]. These in silico tools support formulation selection, dose regimen design, risk
assessment and regulatory interactions, although challenges remain in model validation, incorporation
of patient variability and translation of complex simulations into actionable development and clinical
decisions [10–12,16,18–20].
XI. CLINICAL TRANSLATION AND COMMERCIALIZATION
Clinical translation and commercialization determine whether advanced delivery concepts ultimately
impact patient care, and they involve demonstrating clinical benefit, overcoming scale-up challenges
and navigating complex regulatory pathways [1–3,10,11,14,18–20]. A notable number of
nanomedicines, long-acting injectables, implants and device-based products have reached the market,
illustrating both the promise and the hurdles associated with next-generation systems [1–
3,10,11,14,18–20].
A. Current Marketed Advanced Drug Delivery Systems
Commercial products now include liposomal and lipid nanoparticle formulations, long-acting
injectable depots, transdermal systems, implants and select device-combination products [1–
3,10,11,14,18–20]. Liposomal and other nanocarrier-based medicines have improved the therapeutic
index of anticancer drugs and enabled clinically validated delivery of nucleic acids, while long-acting
depots and implants provide extended dosing intervals for endocrine, psychiatric and other chronic
indications [1–3,10,11,14,18–20]. These examples demonstrate that advanced platforms can achieve
regulatory approval and market adoption when they offer clear clinical advantages and manageable
manufacturing and safety profiles [1–3,10,11,14,18–20].
B. Scale-Up and Manufacturing Challenges
Scaling advanced delivery systems from laboratory to commercial scale presents substantial technical
and operational challenges, particularly for nanoformulations and complex device–drug combinations
[1–3,10,11,14,18–20]. Key issues include maintaining batch-to-batch consistency in particle size,
morphology, encapsulation efficiency, release characteristics and device performance, while
complying with stringent quality and regulatory requirements [1–3,10,11,14,18–20]. Process
optimization, robust in-process controls and appropriate analytical methods are essential, and early
consideration of manufacturability and supply-chain logistics can significantly influence the
feasibility and timelines of clinical and commercial development [1–3,10,11,14,18–20].
C. Regulatory Considerations and Approval Pathways
Advanced and nano-based drug delivery systems face evolving regulatory expectations regarding
characterization, safety assessment and benefit–risk evaluation [1–3,10,11,14,18–20]. Regulatory
agencies have issued frameworks and guidance on nanomedicines and combination products,
emphasizing detailed physicochemical characterization, stability data, toxicology tailored to
nano-specific risks and, where relevant, device performance and human factors studies [1–
3,10,11,14,18–20]. Developers must select appropriate approval routes, design studies that address
both drug and device components when applicable, and consider post-marketing surveillance and
risk-management plans, which together shape the pace and success of translating next-generation drug
delivery systems into clinical practice [1–3,10,11,14,18–20].
XII. Safety, Toxicity, and Regulatory Challenges
Ensuring safety and managing toxicity are central challenges for next-generation and especially
nano-enabled drug delivery systems, which may exhibit complex, size- and surface-dependent
interactions with biological systems [1–3,10,11,18,19]. Global regulatory frameworks are evolving to
address these issues, but gaps remain in standardized testing, long-term risk assessment and
harmonized guidance for advanced formulations [1–3,10,11,14,18–20].
A. Nanotoxicology and Biocompatibility
Nanotoxicology studies have revealed that nanocarriers can induce oxidative stress, inflammation,
immune activation, genotoxicity and organ accumulation, sometimes in ways not predicted by the
bulk material properties of their components [1–3,10,11,18,19]. Toxicity is influenced by particle size,
shape, surface charge, composition, coatings and degradation products, as well as dose, route and
duration of exposure, necessitating case-by-case evaluation and careful design to enhance
biocompatibility [1–3,10,11,18,19]. Biobased and biodegradable materials, surface passivation
strategies and “safe-by-design” approaches are increasingly used to reduce adverse effects while
maintaining or improving delivery performance [1–3,10,11,18,19].
B. Long-Term Safety Concerns
Long-term safety data for many advanced delivery systems, particularly nanomedicines and gene
delivery platforms, remain limited, raising concerns about chronic exposure, delayed toxicity and
accumulation in specific organs or tissues [1–3,10,11,18,19]. Potential issues include persistent
inflammation, immune dysregulation, alterations of barrier integrity (e.g. gut or blood–brain barriers)
and impacts on the microbiome, as well as the possibility of off-target effects and genomic alterations
for gene-editing systems [1–3,10,11,18,19]. Addressing these risks requires extended preclinical
studies, long-term follow-up in clinical trials and robust post-marketing pharmacovigilance tailored to
the specific properties and mechanisms of advanced drug delivery systems [1–3,10,11,14,18–20].
C. Global Regulatory Perspectives
Regulatory agencies in major regions have begun to issue guidance documents and position papers on
nanomedicines, gene therapies and combination products, but regulatory expectations continue to
evolve [1–3,10,11,14,18–20]. Current frameworks emphasize comprehensive physicochemical
characterization, nano-specific toxicological assessment, evaluation of immunogenicity and
biodistribution, and, where applicable, integrated review of both drug and device components [1–
3,10,11,14,18–20]. International harmonization efforts, including ICH initiatives, aim to align quality,
safety and efficacy standards, yet developers must still navigate region-specific requirements and
 uncertainties, underscoring the importance of early and ongoing dialogue with regulators during the
development of next-generation drug delivery systems [1–3,10,11,14,18–20].

XIII. FUTURE PERSPECTIVES AND OPPORTUNITIES

Future development of next-generation drug delivery systems will likely be driven by convergence of
precision medicine, advanced materials, gene and cell therapies, and digital health ecosystems [1–
3,5,10,11,18–20]. Continued integration of responsive materials, targeting strategies and intelligent
control is expected to yield platforms that are more adaptive, patient-specific and clinically impactful
than current sustained and controlled release formulations [2–5,10,11,18–20].
A. Personalized and Precision Medicine
As omics technologies, clinical decision support tools and real-world data become more widely
integrated into healthcare, drug delivery systems will increasingly be tailored to individual patient
profiles rather than population averages. This includes matching delivery platforms to disease
subtype, genetic background, organ function and lifestyle factors, as well as adjusting dose and
release profiles based on continuous or periodic monitoring of biomarkers and treatment response
[2,3,5,10–12,16,18–20]. In this context, modular and reconfigurable systems—such as tunable
nanocarriers, adaptable depots and smart devices—will be particularly valuable because they can be
customized or programmed without fully redesigning the underlying technology [2–4,10–12,16,18–
20].
B. Integration of Multidisciplinary Technologies
The next generation of delivery systems will rely on tight integration of materials science, synthetic
biology, micro- and nano-fabrication, bioelectronics and data science [2–4,6,10–12,16,18–20].
Examples include biohybrid systems that combine living or engineered cells with synthetic carriers,
devices that couple sensing and therapy (theranostics), and nanoelectronic or self-powered platforms
capable of autonomous operation within the body [2–4,6,10–12,16,18–20]. Collaborative efforts
among pharmacologists, engineers, data scientists, clinicians and regulators will be essential to
translate these complex, multidisciplinary technologies into robust, manufacturable and clinically
acceptable products [2–4,10–12,16,18–20].
C. Emerging Trends and Research Directions
Key emerging trends include expansion of exosome and extracellular vesicle platforms, more
sophisticated gene and nucleic acid delivery strategies, organ- and barrier-specific targeting, and
widespread adoption of AI-assisted design and predictive modeling in formulation development
[2,3,6,10–12,16,18–20]. Additional opportunities lie in harnessing the microbiome as a target or
component of delivery systems, leveraging immunomodulatory carriers for vaccination and
immunotherapy, and developing ultra-long-acting and fully implantable systems for chronic diseases
[2–4,10,11,14,18–20]. Realizing these opportunities will require addressing outstanding challenges in
safety, long-term biocompatibility, scalability, cost and equitable access, ensuring that next-generation
drug delivery strategies can benefit diverse patient populations and healthcare settings [1–
3,10,11,14,18–20].

XIV. CONCLUSION
The evolution of drug delivery has progressed from immediate-release formulations through
conventional sustained and controlled release systems toward a diverse landscape of next-generation
strategies that integrate temporal, spatial and patient-specific control of therapy [1–6,10,13,18–20].
 While traditional platforms have improved convenience and reduced peak–trough fluctuations, their
limited adaptability to biological variability, lack of precise targeting and challenges with
macromolecules underscore the need for more sophisticated approaches [1–3,5,18,19].
Emerging delivery paradigms—encompassing targeted, stimuli-responsive, gene and nucleic acid
systems; advanced nanocarriers, hydrogels, biomimetic platforms and exosomes; novel routes such as
microneedle-based transdermal, pulmonary, nasal and oral biologic systems; and implantable or
wearable devices—offer powerful means to address these limitations and support precision medicine
[2–4,6,7,10–12,14–16,18–20]. Their successful translation, however, depends on resolving
outstanding issues in nanotoxicology, long-term safety, manufacturability, cost and regulatory
acceptance, particularly for nano-enabled and combination products [1–3,10,11,14,18–20].
Looking ahead, deeper integration of AI-driven design, predictive modeling, digital health, and
multidisciplinary engineering is expected to yield delivery systems that are increasingly intelligent,
personalized and connected to broader therapeutic ecosystems [2–4,6,10–12,16,18–20]. Achieving
this vision will require coordinated efforts from researchers, clinicians, industry and regulators to
develop safe, effective and accessible next-generation platforms that extend the benefits of advanced
drug delivery beyond specialized settings and into routine clinical practice worldwide [1–
3,10,11,14,18–20].
XV. ACKNOWLEDGMENTS
XVI. CONFLICT OF INTEREST
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