Biologic therapies have transformed the pharmaceutical landscape over the past two decades, offering new treatment options for conditions once thought untreatable. As the pipeline of large molecule drugs continues to expand from monoclonal antibodies and recombinant proteins to complex fusion constructs biologics now account for a significant and growing share of new drug approvals and global sales. Despite their therapeutic power, these molecules come with practical challenges that often limit their accessibility and effectiveness. Chief among these is the need for frequent dosing, which can burden patients with regular clinic visits, self-injections, or infusions that disrupt daily life and strain healthcare resources.
Long-acting injectables (LAIs) have already proven their value for small molecule drugs, dramatically improving adherence in areas like mental health, contraception, and chronic metabolic conditions. For biologics, however, the leap to extended-release formats has been far more difficult to achieve. The promise of LAI depots for large molecules lies in the potential to combine the precision and potency of modern biologics with the convenience and patient-centered benefits that long-acting formats offer. Bridging this gap could redefine treatment paradigms, reduce costs tied to nonadherence, and improve health outcomes for millions worldwide.
Why Long-Acting Formulations Are So Challenging for Biologics
Extending the duration of action for biologics presents a fundamentally different set of obstacles than for small molecules. Unlike small molecules, biologics are large, complex proteins that are inherently sensitive to environmental conditions and prone to structural instability. Maintaining their integrity within a depot system, often over weeks or months, requires careful control of factors like pH, temperature, and moisture — any deviation can lead to denaturation or aggregation that compromises efficacy and safety.1
Biologics are also more likely to provoke unwanted immune responses if their structure changes during storage or release. Designing a depot that releases a biologic at a controlled, predictable rate without triggering immunogenicity demands advanced formulation and material science, as well as sophisticated analytical validation to ensure batch-to-batch consistency.2
Another major barrier is the sheer size of biologics, which typically results in high injection volumes and viscous formulations. Delivering these large volumes subcutaneously or intramuscularly in a single injection can be painful or impractical for patients, limiting the acceptability of depot products. Device design must therefore align with formulation innovations to keep administration feasible and comfortable.
Regulatory pathways further add to the challenge. LAI biologics must demonstrate not only that the active molecule remains stable and effective throughout the intended release period but also that the depot system itself is safe, biocompatible, and reliably manufacturable at scale. These hurdles make it clear that translating the success of LAIs for small molecules into the biologics space requires overcoming multiple layers of scientific and practical complexity.1
State of the Science: Current Technologies and Strategies
Depot Formulations in Use or Development
Despite the inherent complexity, progress is being made toward viable long-acting injectable depots for biologics. Some of the earliest commercial successes have come from therapeutic areas like metabolic disease, where glucagon-like peptide-1 (GLP-1) receptor agonists have demonstrated how formulation and delivery advances can extend dosing intervals from daily to weekly or even monthly.3 Beyond metabolic therapies, several monoclonal antibodies with extended half-lives are now progressing through late-stage development, using either sustained-release formulations or protein modifications to lengthen circulation time.4
These formulations rely on various mechanisms to achieve controlled release. Traditional depot injections deliver the biologic within a matrix that gradually breaks down, while sustained-release microspheres and biodegradable implants can release the active molecule at a predictable rate through polymer erosion. Other approaches, like injectable hydrogels, offer an adaptable platform that can be tailored for different biologics and release profiles, balancing patient comfort with therapeutic consistency.3,4
Key Technological Approaches
One foundational strategy for long-acting delivery involves biodegradable polymers such as poly(lactic-co-glycolic acid) (PLGA). PLGA-based microspheres and implants have been widely studied for their ability to encapsulate biologics and release them steadily as the polymer matrix undergoes hydrolytic degradation. This approach has shown promise for proteins and peptides that require steady plasma levels over weeks or months.3
Nanoparticle systems are another area of intense research. Lipid nanoparticles and polymeric nanoparticles can encapsulate sensitive biologic molecules, shielding them from degradation while controlling their release. Advances in nanoparticle surface chemistry have further improved targeting and reduced immunogenicity, helping to bridge the gap between lab-scale promise and clinical utility.5
In situ gelling systems offer an alternative path to depot formation. These formulations are injected as a liquid that rapidly forms a semi-solid depot under physiological conditions, eliminating the need for pre-formed implants and simplifying administration. Such systems can be tuned to respond to temperature or pH changes in the body, providing flexibility in depot design and potential for patient-friendly delivery.4
Protein engineering strategies are equally vital. Techniques such as Fc-fusion, PEGylation, and albumin-binding extend the circulating half-life of biologics by reducing clearance rates, effectively turning the body’s own biology into part of the sustained-release solution. These modifications can be combined with physical depot systems for additional duration or used alone where appropriate.2,6
Finally, some emerging approaches push the definition of a depot even further. For example, depot vaccines and gene-based therapies aim to create an in situ production system inside the body, where a single administration induces cells to produce a therapeutic protein over an extended period. While still largely experimental, these strategies hint at how the boundaries of controlled release may expand in the years ahead.6
Real-World Case Studies and Early Successes
While the majority of biologic LAIs are still in development, several real-world examples illustrate the tangible impact these innovations can have on patient care and adherence. Long-acting GLP-1 receptor agonists for type 2 diabetes stand out as a clear success story. By extending dosing from daily to weekly or monthly, these formulations have improved patient compliance and delivered better glycemic control while reducing the treatment burden.2
In other areas, monoclonal antibodies (mAbs) with extended half-lives are beginning to reshape treatment options for chronic conditions that benefit from sustained suppression or prophylaxis. One promising frontier is HIV prevention, where investigational mAb therapies aim to provide long-lasting protection with infrequent dosing, addressing adherence challenges that have historically limited the effectiveness of daily oral regimens.1
Important lessons can also be drawn from the long-established use of LAIs for small molecules in psychiatry and reproductive health. Depot antipsychotics have transformed care for patients with schizophrenia and bipolar disorder, conditions where medication nonadherence can lead to relapse and hospitalization. Similarly, injectable contraceptives that provide months-long protection have shown that patient preference often leans strongly toward fewer administrations, even when self-administration is feasible. These precedents highlight how convenience, dosing frequency, and perceived control over treatment play critical roles in real-world uptake and success.2
Several companies and research groups are now building on these insights to adapt LAI strategies for large molecules. Innovations include novel excipients to improve protein stability, new polymer systems that match the unique release kinetics of biologics, and integrated device solutions that make high-volume injections more acceptable and manageable. As more programs advance through clinical development, the field continues to gain valuable data on what works and where further breakthroughs are still needed to deliver on the full promise of biologic depots.1
Remaining Barriers and R&D Frontiers
Despite notable advances, several barriers continue to limit the widespread adoption of LAIs for biologics. One of the most immediate practical challenges is managing injection volume. Many biologics require relatively large doses to maintain therapeutic levels, which can result in high injection volumes and viscous formulations that are difficult or uncomfortable to administer. Developing delivery devices that can handle these volumes painlessly — whether through novel syringes, autoinjectors, or on-body pumps — remains a critical area of innovation.1
Formulation challenges are equally significant. Biologics are sensitive to physical and chemical stresses that can occur during encapsulation or depot formation. Protein aggregation or denaturation within a polymer matrix, for example, can reduce potency or trigger unwanted immune responses. Achieving predictable release kinetics without compromising structural integrity demands advanced formulation techniques and thorough stability studies at every stage of development.4
Patient-centric design must also guide every aspect of depot development. Even the most technically elegant formulation will fail if patients are unwilling or unable to use it. Questions around self-injection, device usability, injection site reactions, and follow-up care all shape how likely patients are to adopt and adhere to long-acting biologic therapies. Engaging patients early to understand preferences and tolerances is essential to bridge the gap between lab success and market viability.1
Regulatory clarity and chemistry, manufacturing, and controls (CMC) requirements pose additional hurdles. Manufacturers must demonstrate that both the biologic and the delivery system maintain consistent quality, safety, and performance over time. This dual burden of proving stability for a complex molecule and the biocompatibility of an advanced depot system adds layers of cost and complexity to the development process. Ensuring that production can scale reliably from pilot batches to commercial volumes without compromising product performance is another critical challenge, particularly as supply chains for specialized polymers and excipients evolve alongside the biologics themselves.4
Together, these barriers underline why partnerships between innovators, contract development and manufacturing organizations (CDMOs), device companies, and regulators will remain central to overcoming the technical and practical frontiers that still stand in the way of making biologic depots a routine part of modern care.
Outlook: What Will It Take to Bring LAI Biologics to Scale?
For long-acting injectable biologics to become routine clinical options rather than niche solutions, several scientific and industry advances must converge in the coming years. First, new breakthroughs in materials science are needed to refine and expand the range of biocompatible polymers, nanoparticles, and hybrid systems capable of protecting sensitive proteins while delivering predictable, extended release. Complementing these physical systems, more sophisticated predictive modeling will help developers simulate release profiles, stability, and patient-specific pharmacokinetics, streamlining formulation design and reducing costly trial-and-error experimentation.2
Equally important is the continued evolution of delivery devices. As injection volumes grow and viscosity remains a hurdle, next-generation autoinjectors, wearable pumps, or even implantable systems will need to be designed with patient comfort and usability at the forefront. Lessons learned from early biologic depots, such as managing injection-site reactions and ensuring consistent administration by non-clinicians, will shape the requirements for future platforms.6
Scaling these innovations will demand strong partnerships across the supply chain. CDMOs with deep expertise in both biologics and complex formulations will play an increasingly pivotal role, as few biopharma companies can manage the full spectrum of material sourcing, sterile processing, device integration, and regulatory validation alone.2
Aligning product development with real-world patient needs and payer expectations will also be critical. Early evidence suggests that when given the choice, many patients prefer fewer injections and longer dosing intervals, even if the delivery device is slightly more complex. Health systems and insurers, meanwhile, stand to benefit from reduced nonadherence and fewer clinic visits. Capturing and applying this data to guide design, messaging, and reimbursement models will help ensure that new LAI biologics are not only scientifically viable but also commercially successful.6
Finally, regulatory harmonization and clearer global standards for long-acting biologics will help reduce uncertainty and duplication in development pathways. Consistent guidance on acceptable materials, device standards, release testing, and stability validation will make it easier for developers to scale promising concepts across markets. Together, these technical, collaborative, and policy advances will determine whether the next decade turns the promise of biologic depots into a new standard of care.
Conclusion
LAI depots for biologics represent one of the most promising frontiers in modern drug delivery. By combining the therapeutic power of complex large molecules with the convenience and adherence benefits proven by LAIs for small molecules, these systems have the potential to transform how chronic and serious conditions are managed worldwide. For patients, longer dosing intervals mean fewer injections, reduced clinic visits, and improved quality of life. For health systems, they offer a pathway to better outcomes through greater adherence and lower total treatment costs, an increasingly urgent priority as biologics continue to grow as a share of the global pharmaceutical market.2,3
However, the road ahead remains challenging. Success will depend on solving technical barriers around stability, release kinetics, injection volume, and manufacturability, while aligning innovations with patient preferences and regulatory expectations. Early examples and emerging case studies show that these obstacles can be addressed, but scaling such solutions demands sustained collaboration across disciplines and sectors, from materials science to device engineering and advanced manufacturing.1,4
Achieving the full promise of LAI biologics will require continued investment, robust partnerships with specialized CDMOs, and clear regulatory pathways that foster both safety and speed to market. As lessons learned from small molecule LAIs are translated into this more complex arena, the industry has an opportunity to bridge decades of innovation and redefine the standard of care for millions. With concerted effort, the next generation of biologic depots could deliver not just longer-lasting therapies, but more durable health and greater access across the globe.5,6
References
1. Gonella, Andrea, et al. “Long-acting injectable formulation technologies: challenges and opportunities for the delivery of fragile molecules.” Expert Opinion on Drug Delivery. 19: 927–944 (2022).
2. Singh, Satinder and Pratima Srivastava. “Long-acting injectables for biologics: Current landscape and future perspective.” PharmaPhorum. Accessed 1 Jul. 2025.
3. Schwendeman, Steven P, et al. “Injectable controlled release depots for large molecules.” J. Control. Release. 190: 240–253 (2015). https://pmc.ncbi.nlm.nih.gov/articles/PMC4261190/
4. dos Santos, Ana Gomes. “Novel Approaches to Achieve Long-Acting Formulations for Biologics.” The Conference Forum. 29 Mar. 2024.
5. Huang, Jim and Shaukat Ali. “Long-Acting Injectable Nanoparticle Formulations.” American Pharmaceutical Review. 1 Mar. 2023.
6. D’Aquino, Andrea I, et al. “Use of a biomimetic hydrogel depot technology for sustained delivery of GLP-1 receptor agonists reduces burden of diabetes management.” Cell Reports Medicine. 4: 101292 (2023).